NET AND SOLID NUTRITIONAL COMPOSITION WITH HIGH PROTEIN AND LOW CALORIE

专利摘要:
High protein and low calorie nutritional composition for stimulating muscle protein synthesis. The present invention relates to the use of a high protein, low calorie nutritional composition for use in preventing or treating a disease or health condition in a mammal involving muscle deterioration as well as nutritional compounds of the invention. high protein and low calorie composition specific to stimulate muscle protein synthesis in a mammal. In particular, the invention relates to the use of a neuronal composition comprising per 100 kcal: (i) at least about 12 g of proteinaceous matter comprising at least about 80% by weight of whey protein, with respect to total proteinaceous material and comprising at least approximately 11% by weight of leucine relative to total proteinaceous material, of which approximately 20% by weight is in a free form relative to total leucine, (ii) a fat source and a source of digestible carbohydrates for the prevention or treatment of a disease or condition involving muscle deterioration in a mammal, especially an elderly mammal, wherein the nutritional composition is administered in the form of 1 up to 2 servings a day, each serving between 80 and 200 kcal.
公开号:BR112012015753B1
申请号:R112012015753-1
申请日:2010-12-23
公开日:2019-11-26
发明作者:Yvette Charlotte Luiking；George Verlaan；Marion Jourdan
申请人:N.V. Nutricia；
IPC主号:

专利说明:

Descriptive Report of the Invention Patent for NET AND SOLID NUTRITIONAL COMPOSITION WITH HIGH PROTEIN CONTENT AND LOW CALORIE.
FIELD OF THE INVENTION [001] The present invention relates to the use of a nutritional composition with a high protein content and low calorie suitable for the prevention or treatment of a disease or state of health in a mammal, which involves muscle deterioration , as well as specific high-protein, low-calorie nutritional compositions suitable for stimulating muscle protein synthesis in a mammal.
BACKGROUND OF THE INVENTION [002] Age-related involuntary loss of muscle mass and strength occurs during aging and is called sarcopenia [1]. Regarding the degenerative loss of skeletal muscle mass, it occurs at a rate of 3-8% per decade after the age of 30 and accelerates from the age of 60. Both impaired muscle mass and muscle strength are related to age-related loss of muscle function.
[003] The main drivers of skeletal muscle mass maintenance are stimulating muscle protein synthesis and inhibiting muscle protein breakdown. Muscle protein synthesis is stimulated by the biological availability of amino acids (in particular leucine) and physical activity. Thus, both contribute to a positive net balance of muscle protein (that is, the difference between muscle protein synthesis and protein breakdown; liquid muscle protein synthesis). It is important to maintain muscle mass and prevent muscle deterioration and muscle wasting. Protein starvation and muscle inactivity, which often occur with aging and disease, result in a failure to maintain
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2/52 muscle mass, with muscle wasting. With aging, there is an imbalance between muscle protein synthesis and breakdown. In addition, the anabolic response to decreases in diet, which additionally contributes to insufficient liquid protein synthesis and subsequent muscle deterioration with aging. [1-6]. Compared with younger adults, the elderly need higher levels of amino acids in the blood - especially leucine - to stimulate muscle protein synthesis. This phenomenon of reduced muscle response capacity, which occurs in the elderly, is called anabolic resistance that leads to muscle deterioration. Thus, it is beneficial to have a nutritional composition, especially for the elderly, to overcome this resistance and stimulate the synthesis of muscle protein (liquid). In fact, a so-called source of fast protein with a high leucine content has proven to be more efficient in the elderly than a similar amount of protein with a low leucine content or a slow protein [7, 8]. Thus, an adequate anabolic stimulus in the muscle still has the potential to activate the muscle protein signaling pathway and thereby cause muscle protein synthesis in a mammal, especially in an elderly mammal.
[004] Specific amino acids are known for their stimulating effect on muscle protein synthesis; these amino acids are considered anabolic. Of the amino acids, the essential amino acids (EAAs) in particular are able to stimulate muscle protein synthesis in the elderly, whereas non-EAAs may have lesser benefit for muscle anabolism [9, 10]. The elderly need a higher dose of AAS (> 6.7 g of AAS), supplied in the form of a cake, to stimulate muscle anabolism [11, 12]. Thus, the lower age-related responsiveness could also be resolved by increasing leucine
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3/52
1.7 g to 2.8 g leucine in a 6.7 g mixture of EAAs) [8]. Leucine also acts as a signaling molecule [13]. The importance of leucine for muscle protein synthesis has also been confirmed for intact protein sources with varying levels of leucine (sources of whey protein and casein) in an animal study. In this study, elderly rats showed a gradual increase in muscle protein synthesis concomitant with an increase in the level of leucine in the protein source, as is the case for whey protein [14]. In healthy elderly people, whey protein also resulted in a higher total body protein synthesis rate with casein protein [15].
[005] The synthesis of muscle protein is positively related to the concentration of extracellular amino acids [16] and the appearance of intracellular amino acids in the muscle [17]. An increase in the concentration of serum amino acids can stimulate muscle protein synthesis, but higher levels of essential amino acids, and especially leucine, are needed in the elderly [8, 11]. Therefore, strategies that can significantly increase leucine levels in the blood appear useful in helping to restore the acute anabolic response to food in the elderly. The levels of amino acids in the blood after eating can be influenced by the type of food. Part of the diet's amino acids are extracted in the intestine and liver for local protein synthesis (ie, splanchnic extraction or sequestration). The rest of the amino acids appear in the systemic blood circulation and reach other organs, with muscle as the largest protein reservoir [18]. Dietary proteins vary in amino acid composition, digestion rate and splanchnic extraction level, all influencing the subsequent appearance of amino acids in the circulation. Due to the fact that whey protein contains higher levels of leucine than casein protein, levels
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4/52 of leucine in serum are higher after ingestion of whey protein [15]. Previous studies comparing casein protein and whey protein have identified casein as a slow protein and whey protein as a fast protein, with reference to the rate of appearance in the circulation of amino acids [7, 19]. The rate of digestion is an important factor in this concept of slowness / speed [20] and is partially determined by the rate of gastric emptying. In the elderly, the appearance of amino acids in the blood is reduced [15], because splanchnic extraction is higher [21, 22] and the rate of digestion / gastric emptying is slower [23] than in young people.
[006] Following the need to provide higher levels of amino acids to increase the biological availability of anabolic amino acids to stimulate muscle protein synthesis in a mammal, especially in an elderly human, the levels of serum amino acids in the elderly after ingestion of Low calorie nutritional formulations containing high whey protein content have been studied. The clinical study evaluated the biological availability of amino acids in the elderly after ingesting such nutritional formulation. SUMMARY OF THE INVENTION DESCRIPTION [007] Surprisingly, the inventors found that essential amino acids, in particular leucine, exhibited a greater biological availability of amino acids to stimulate muscle protein synthesis and subsequent muscle mass through the use of a new formulation high-calorie nutritional protein. Without being bound by theory, the hypothesis has been raised that amino acids reach circulation more quickly and reach higher levels in the blood when dietary protein is supplied in a low-calorie composition compared to a high-calorie composition, preferably using protein of whey, although
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5/52 the effect is the same, but less so for casein. In the course of this patent application, this effect will be called the low energy effect. This low-energy effect could beneficially be used to treat people suffering from any disease or health condition, the prevention and treatment of which are related to the synthesis of muscle protein, in particular, sarcopenia, a disease that involves muscle deterioration with insufficient (liquid) muscle protein synthesis and muscle deterioration, associated with aging.
DETAILED DESCRIPTION OF THE INVENTION [008] According to one aspect, the present invention relates to a nutritional composition comprising per 100 kcal:
(i) at least approximately 12 g of proteinaceous matter which comprises at least approximately 80% by weight of whey protein, with respect to the total proteinaceous matter and which comprises at least approximately 11% by weight of leucine, with respect to the matter total proteinaceous, of which at least approximately 20% by weight is in a free form, relative to total leucine, (ii) a source of fat and a source of digestible carbohydrates, for use in preventing or treating a disease or a state of health that involves muscle deterioration in a mammal, in which the nutritional composition is administered in the form of 1 to 2 servings daily, each serving comprising between 80 and 200 kcal.
[009] In the context of this patent application, the term at least still includes the starting point of the open band. For example, an amount of at least 95% by weight means any amount. Petition 870190088424, 06/09/2019, pg. 18/90
6/52 of 95% by weight or greater.
[0010] In the context of this patent application, the term approximately means a deviation of 5% or less from the value provided, such as 4%, 3%, 2%, 1% or less than 1%. For example, an amount of approximately 12 g means any amount equal to 12 g ± 0.6 g, that is, any amount in the range of 11.4 to 12.6 g. The reason for using the term roughly is to take into account the uncertainty associated with the detection method or the variability of the production method when it refers to the production of a nutritional composition.
[0011] In the context of this patent application, the term is either defined as and / or unless otherwise specified. Thus, the expression A or B comprises the individual members A and B, as well as the combined members A and B.
[0012] In the context of this patent application, the expressions one, one, o and a imply both the singular and the plural of the name to which they refer. Thus, the expression a protein means one or more proteins.
Proteinaceous matter [0013] The nutritional composition according to the invention comprises at least approximately 12 g of proteinaceous matter per 100 kcal. By the term proteinaceous matter is meant a protein or any 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. Preferably, proteinaceous matter originates from dairy proteins, such as whey protein and casein. Amino acids are essentially L-amino acids since only Lamino acids are available metabolically.
[0014] Preferably, the composition comprises at least
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7/52 approximately 12.5 g, at least approximately 13 g, at least approximately 13.5 g and more preferably approximately 14 g of proteinaceous matter per 100 kcal.
[0015] According to another embodiment, the nutritional composition according to the invention comprises at least approximately 48 en% proteinaceous matter per 100 kcal. Preferably, the composition comprises at least approximately 50 en%, at least approximately 52 en%, at least approximately 54 en% and most preferably approximately 56 en% proteinaceous per 100 kcal.
The proteinaceous material according to the invention comprises at least approximately 80% by weight of whey protein, preferably at least approximately 85% by weight of whey protein, preferably at least approximately 90% by weight and more preferably approximately 95% by weight of whey protein.
[0017] As discussed earlier, whey protein is considered a fast protein referring to the rate of appearance in the circulation of amino acids. The whey protein can be an intact whey protein, a hydrolyzed whey protein, a microparticular whey protein, a nanoparticular 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. Hydrolyzed whey protein suffers from the drawback that it has an unpleasant taste.
[0018] As a source of whey protein that will be used in the present invention, any commercially available source of whey protein can be used, i.e.
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8/52 whey protein obtained by any process for the preparation of whey protein known in the art, as well as whey protein fractions prepared from it or the proteins that make up the mass of whey proteins milk that are β-lactoglobulin, α-lactalbumin and whey albumin, such as liquid whey protein or whey protein in powder form, such as whey protein isolate (WPI) or protein concentrate of whey (WPC). The whey protein concentrate is rich in whey proteins, but it also contains other components such as fat, lactose and glycomacroprotein (GMP), a non-globular protein related to casein. Typically, whey protein concentrate is produced by membrane filtration. On the other hand, the whey protein isolate consists primarily of whey proteins with minimal amounts of fat and lactose. The whey protein isolate generally requires a more stringent separation process such as a combination of microfiltration and ultrafiltration or ion exchange chromatography. It is generally understood that a whey protein isolate refers to a mixture in which at least 90% by weight of the solids are whey proteins. A whey protein concentrate is understood to have a percentage of whey proteins between the initial amount in the by-product (approximately 12% by weight) and a whey protein isolate. 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 acidic casein, native whey protein, obtained through microfiltration of milk or whey rennet milk, obtained as a by-product in the manufacture of rennet casein, can be used as a source of whey proteins.
[0019] In addition, whey proteins can originate
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9/52 all types of mammalian animal species, such as, for example, cows, sheep, goats, horses, buffaloes and camels. Preferably, the whey protein is of bovine origin.
[0020] Preferably, the source of whey protein proteins is available as a powder, preferably the source of whey protein proteins is a WPC or WPI.
[0021] According to another embodiment, the proteinaceous material according to the invention comprises at least approximately 45% by weight of essential amino acids (EAA), preferably at least approximately 47% by weight and more preferably at least approximately 50% by weight of EAA. The essential amino acids are amino acids selected from the group of isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), threonine (Thr), tryptophan (Trp) and valine (Val).
[0022] Since the native whey protein comprises at most (depending on the source) approximately 45% by weight of EAA, it may be necessary to add EAA's in the nutritional composition, such as in the form of amino acids or peptides. It was observed that approximately 45% by weight of total EAA is a minimum amount present in the nutritional composition.
[0023] The proteinaceous material according to the invention comprises at least approximately 11% by weight of leucine. Since natural whey protein comprises at most (depending on the source) approximately 11% by weight of leucine, it may be necessary to add leucine to the nutritional composition, such as in the form of amino acids or peptides. It was observed that approximately 11% by weight of total leucine is a minimum amount present in the nutritional composition.
[0024] Preferably, the proteinaceous material according to the invention comprises at least approximately 12% by weight,
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10/52 preferably at least approximately 12.5% by weight, more preferably at least approximately 13% by weight of leucine, more preferably at least approximately 14% by weight of leucine.
[0025] Total leucine comprises at least approximately 20% by weight, preferably at least approximately 22.5% by weight, preferably at least approximately 26% by weight of leucine in a free form, in relation to the amount of total leucine. The total leucine comprises at most approximately 70% by weight, preferably at most approximately 60%, preferably at most approximately 50% of leucine in a free form, in relation to the amount of total leucine. 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, in the form of a base, a salt or a chelate.
[0026] According to another embodiment, the proteinaceous material according to the invention comprises a total amount of leucine, valine and isoleucine in a ratio of leucine: valine: isoleucine of approximately 1.7-3: 1: 1. Alternatively, the weight ratio of leucine: (valine + isoleucine) is approximately 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, in free form as bases or salts or as peptides.
Fat and carbohydrates [0027] The low calorie nutritional composition according to the invention must comprise a fat source and a carbohydrate source. The presence of these components prohibits the excessive use of protein as an energy source instead of stimulating synthesis
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11/52 of muscle protein.
[0028] The total amount of energy provided by fat and carbohydrates (digestible and indigestible) must combine the total energy provided by proteinaceous matter. Therefore, the total amount of fat and carbohydrates per 100 kcal should be at most approximately 52 en%, in particular at most approximately 50 en%, preferably at most approximately 48 en%, most preferably at most approximately 46 en% or approximately 44 en %.
[0029] The amount of energy supplied by fat and carbohydrates respectively can vary within wide limits, as long as both components are present. According to one embodiment, the amount of fat can vary between 10 and 35 en%, preferably between 15 and 30 en%. According to a modality, the amount of carbohydrate can vary between 10 and 35 en%, preferably between 15 and 30 en%. According to one modality, the sum of the amounts of fat and carbohydrate can vary between 10 and 60 en%.
[0030] In a preferred embodiment, the nutritional composition according to the invention comprises approximately 2 g of fat and approximately 6.2 to approximately 6.4 g of carbohydrates that can be digested per 100 kcal.
[0031] In an additionally preferred embodiment, the nutritional composition according to the invention comprises approximately 2 g of fat and approximately 6.4 g of carbohydrates that can be digested per 100 kcal.
[0032] Regarding the type of fat, a wide choice is possible, as long as the fat is of food quality.
[0033] The fat can be animal fat or vegetable fat or both. Although animal fats such as lard
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12/52 pork or butter have essentially equivalent caloric and nutritional values and can be used interchangeably, vegetable oils are highly preferred in the practice of the present invention due to their easy availability, ease of formulation, absence of cholesterol and lower concentration of acids saturated fatty. In one embodiment, the present composition comprises rapeseed oil, corn oil or sunflower oil. Fat may include a source of medium chain fatty acids (mainly 8 to 10 carbon atoms in length), such as medium chain triglycerides (MCT), a source of long chain fatty acids (mainly at least 18 carbon atoms long), such as polyunsaturated fatty acids (PUFA's) such as omega-3 and omega-6 fatty acids, including EPA, DHA and long chain triglycerides (LCT) and phospholipid-bound fatty acids such as EPA or DHA bound to phospholipid 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 poor nutrient absorption. Sources of LCT, such as canola oil, rapeseed oil, sunflower oil, soybean oil, olive oil, coconut oil, palm oil, flaxseed oil, marine oil or corn oil are beneficial because it is known that LCTs can modulate the immune response in the human body. Regardless of the anti-inflammatory properties of omega-3 fatty acids, omega-3 fatty acids, such as EPA and DHA, can stimulate muscle protein synthesis by increasing muscle anabolic signaling activity. Thus, according to a preferred embodiment, the fat source comprises omega-3 fatty acids, in particular EPA and DHA.
[0034] Regarding the type of carbohydrates, a choice is possible
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13/52 wide, as long as the carbohydrates are of food quality. Carbohydrates that can be digested positively influence an individual's energy level and add the advantageous effect of the nutritional composition according to the invention. The carbohydrate that can be digested can comprise simple or complex carbohydrates or any mixture of them. Glucose, fructose, sucrose, lactose, trehalose, palatinose, corn syrup, malt, maltose, isomaltose, partially hydrolyzed corn starch, maltodextrins, oligo- and polysaccharides are suitable for use in the present invention.
The liquid enteral nutritional composition according to the invention can optionally be fortified 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 pectin degradation product with a DP of 2 - 250) or other pectin degradation products). 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 non-digestible carbohydrates. Dietary fibers include undigested oligosaccharides that have 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 comprise fructo-oligosaccharides (FOS), trans-galacto-oligosaccharides (TOS), xylo-oligosaccharides (XOS), soy oligosaccharides and the like. Optionally, even 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
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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 or below 0.6 g / 100 kcal. The amount of thickened polysaccharides such as carrageenans, xanthans, pectins, galactomannans and other polysaccharides that cannot be digested with high molecular weight (DP> 50) is preferably low, that is, less than 20% of the weight of the fiber fraction or less of 1 g / 100 kcal. Instead, hydrolyzed polysaccharides such as hydrolyzed pectins and galactomannans can be advantageously included.
[0036] A preferred fiber component is an oligosaccharide that cannot be digested with a chain length (DP) of 2 to 10, for example, Fibersol® (resistant oligoglucose), in particular hydrogenated Fibersol® or a mixture of oligosaccharides that they have a DP of 2 to 10, such as fructooligosaccharides or galactooligosaccharides (GOS), which can also contain a small amount of superior saccharides (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.
[0037] 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.
[0038] In another embodiment of the present invention, the composition according to the invention may comprise a mixture of neutral and acidic oligosaccharides as disclosed in WO 2005/039597 (N.V. Nutricia), which is incorporated herein by reference in its entirety
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15/52. More particularly, the acid oligosaccharide has a degree of polymerization (DP) between 1 and 5000, preferably between 1 and 1000, more preferably between 2 and 250, even more preferably between 2 and 50, more preferably between 2 and 10. If a mixture of acid oligosaccharides with different degrees of polymerization is used, the average DP of the acid oligosaccharide mixture is preferably between 2 and 1000, more preferably between 3 and 250, even more preferably between 3 and 50. The acid oligosaccharide can be a homogeneous carbohydrate or heterogeneous. Acid oligosaccharides can be prepared from pectin, pectate, alginate, chondroitin, hyaluronic acids, heparin, heparan, bacterial carbohydrates, sialoglycans, fucoidan, fuco-oligosaccharides or carrageenan and are preferably prepared from pectin or alginate. Acid oligosaccharides can be prepared using the methods described in WO 01/60378, which are 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 herein, the degree of methoxylation (also referred to as DE or degree of esterification) is intended to mean the extent to which the groups of free carboxylic acids contained in the polygalacturonic acid chain have been esterified (for example, by methylation). The acidic oligosaccharides are preferably characterized by a degree of methoxylation above 20%, preferably above 50% and even more preferably above 70%. Preferably the acidic oligosaccharides have a degree of methylation 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.
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The term neutral oligosaccharides as used in the present invention refers to saccharides that have a degree of polymerization of monose units that exceeds 2, more preferably that exceeds 3, even more preferably that exceeds 4, more preferably that exceeds 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 and preferably do not have acidic 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 that 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 refer to units that have a closed ring structure, preferably hexose, for example, the forms of pyranose or furanose. 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, Dgalactopyranose, ribose, glucose, xylose and derivatives thereof, calculated on the total number of monose units contained there. Suitable neutral oligosaccharides are preferably fermented by the intestinal flora. Preferably, the oligosaccharide is selected from the group consisting of: cellobiosis (4-O-3-D-glucopyranosyl-Dglycosis), cellodextrins ((4-O-3-D-glucopyranosyl) nD-glucose), B-cyclodextrins (Molecules cyclic D-glucose with α-1-4 bond; αcyclodextrin-hexamer, β-cyclodextrin-heptamer and γ-cyclodextrinoctamer), undigested dextrin, gentiooligosaccharides
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17/52 (mixture of glucose residues with β-1-6 bond, some 14 bonds), gluco-oligosaccharides (mixture of α-D-glucose), isomaltooligosaccharides (linear glucose residues with α-1-6 bond with some bonds 1-4), isomaltose (6-OaD-glucopyranosyl-D-glucose); isomaltriosis (6-OaD-glucopyranosyl- (1-6) -aD-glucopyranosyl-D-glucose), panose (6-OaD-glucopyranosyl- (1 -6) -aD-glucopyranosyl- (1-4) D-glucose) , leukrose (5-OaD-glucopyranosyl-D-fructopyranoside), palatinose or isomaltulose (6-OaD-glucopyranosyl-D-fructose), teanderose (OaD-glucopyranosil- (1-6) -OaD-glucopyranosyl- (1-2) -B-Dfrutofuranoside), D-agatosis, D- / yxohexulose, lactosaccharose (O-3-Dgalactopyranosyl- (1-4) -OaD-glucopyranosyl- (1-2) -eD-fructofuranoside), α-galacto- oligosaccharides including raffinose, stachyose and other soy oligosaccharides (OaD-galactopyranosyl- (1-6) -a-Dglucopyranosyl-eD-fructofuranoside), β-galacto-oligosaccharides or transgalacto-oligosaccharides (eD-galactopyrosyl- (1- [eD-glucopyranosyl] n- (1-4) α-D glucose), lactulose (4-OeD-galactopyranosyl-Dfructose), 4'-galatosilactose (OD-galactopyranosil- (1-4) -Oe-Dglucopyranosil- (1 -4) -D-glucopyranose), synthetic galacto-oligosaccharide (neogalactobiosis, isogalactobiosis, galsaccharose , isolactose I, II and III), fructans - Levana (3-D- (2A6) -fructofuranosyl) n α-Dglucopyrananoside), fructans - Inulin (3-D - ((2A1) fructofuranosyl) n α- D-glucopyranoside), 1 fe-fructofuranosylnistose (β-D ((2A1) -frutofuranosyl) n BD-fructofuranoside), xylo-oligosaccharides (BD - ((1 A4) -xylose) n, lymphose, lactosaccharose and arabinooligosaccharides.
[0040] According to an additional preferred embodiment, the neutral oligosaccharide is selected from the group consisting of fructans, fructooligosaccharides, dextrins that cannot be digested with galacto-oligosaccharides (including transgalacto-oligosaccharides), xylooligosaccharides, arabinooligosaccharides, gluco-oligosaccharides, glucosaccharides,
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18/52 manooligosaccharides, fuco-oligosaccharides and mixtures thereof. Most preferably, the neutral oligosaccharide is selected from the group consisting of fructooligosaccharides, galacto-oligosaccharides and transgalacto-oligosaccharides.
[0041] Suitable oligosaccharides and their production methods are further described in Laere KJM (Laere, KJM, Degradation of structurally different non-digestible oligosacharides by intestinal bacteria: glycosylhydrolases of Bi. Adolescentis. PhD-thesis (2000), Wageningen Agricultural University , Wageningen, The Netherlands), the entire contents of which are hereby incorporated by reference. Transgalacto-oligosaccharides (TOS) are, for example, sold under the trade name Vivinal ^TM (Borculo Domo Ingredientes, Netherlands). Undigested dextrin, which can be produced through corn starch pyrolysis, comprises α (1 ^ 4) and α (1 -> 6) glycosidic bonds, which are present in native starch and contain 1 ^ 2 bonds and 1 ^ 3 and levoglucosan. Due to these structural characteristics, dextrin that cannot be digested contains well-developed branched particles that are partially hydrolyzed by human digestive enzymes. Various other commercial sources of indigestible oligosaccharides are readily available and are known to the person skilled in the art. For example, transgalactooligosaccharide is available from Yakult Honsha Co., Tokyo, Japan. Soy oligosaccharide is available from Calpis Corporation distributed by Ajinomoto USA Inc., Teaneck, NJ
[0042] In an additionally preferred embodiment, the composition according to the invention comprises an acid oligosaccharide with a DP between 2 and 250, prepared starting from pectin (such as hydrolyzed pectin (an acid oligosaccharide (AOS)) and low viscosity pectin ), alginate and mixtures thereof; and a neutral oligosaccharide, selected from the group of fructans, fructooligosaccharides,
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19/52 undigested dextrins, galacto-oligosaccharides including transgalacto-oligosaccharides, xylooligosaccharides, arabinooligosaccharides, gluco-oligosaccharides, manooligosaccharides, fucooligosaccharides and mixtures thereof.
[0043] In an additionally preferred embodiment the composition according to the invention comprises chemically distinct neutral oligosaccharides. It has been observed that the administration of acid oligosaccharides combined with two chemically distinct neutral oligosaccharides provides an optimal synergistic immune stimulating effect. Preferably the composition according to the invention comprises:
- acidic oligosaccharides as defined above (preferably low viscosity pectin);
- a neutral galactose-based oligosaccharide (of which more than 50% of the monose units are galactose units), preferably selected from the group consisting of galactooligosaccharide and transgalacto-oligosaccharide; and
- a neutral fructose or glucose based oligosaccharide (of which more than 50% of the monose units are fructose or glucose, preferably fructose units), preferably inulin, fructan or fructooligosaccharide, more preferably long-chain fructooligosaccharide (with an average DP 10 to 60).
[0044] Preferably, the nutritional composition further comprises one or more dietary fibers selected from the group of short-chain GOS, long-chain FOS, inulin and low-viscosity pectin.
[0045] In a particular preferred embodiment, the nutritional composition comprises per 100 kcal:
(ii) approximately 14 g of proteinaceous matter comprising approximately 95% by weight of whey protein from
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20/52 milk, in relation to total proteinaceous matter and comprising at least approximately 14% by weight of leucine, in relation to total proteinaceous matter, of which at least approximately 26% by weight is in a free form, in relation to leucine total, (iii) approximately 2 g of fat and approximately
6.2 to approximately 6.4 g of digestible carbohydrates, for the prevention or treatment of a disease or health condition that involves muscle deterioration in a mammal, where the nutritional composition is administered in the form of 1 up to 2 servings daily, each serving comprising approximately 150 kcal.
[0046] In another particular preferred embodiment, the nutritional composition comprises per 100 kcal:
(ii) approximately 14 g of proteinaceous matter which comprises approximately 95% by weight of whey protein, in relation to the total proteinaceous matter and which comprises at least approximately 14% by weight of leucine, in relation to the total proteinaceous matter, of the which at least approximately 26% by weight are in a free form, relative to total leucine, (iii) approximately 2 g of fat and approximately
6.2 g of digestible carbohydrates, for use in the prevention or treatment of a disease or health condition that involves muscle deterioration in a mammal, where the nutritional composition is administered in the form of 1 to 2 servings daily, each portion comprising approximately 150 kcal.
Micronutrients [0047] The elderly are at risk for micronutrient deficiencies, which is partly due to the fact that their energy intake
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21/52 is often reduced while many micronutrient recommendations increase [24]. As a result, 25-60% of the elderly do not meet the recommendations for micronutrient intake and deficiencies of vitamins A, C, D, E, B6, folic acid, B12, calcium, magnesium and zinc are commonly reported [25-27] . In addition, micronutrient deficiencies are associated with frailty. Low intake of vitamin D, E, C and folate was associated with frailty [28] and low levels in serum of carotenoids, vitamin E, vitamin D, selenium and zinc were observed in the elderly with frailty versus without frailty [29].
[0048] Of the micronutrients, selenium, zinc, carotenoids, vitamin A, vitamin C and vitamin E all have antioxidant properties. In relation to the published observation on the reversion by antioxidant supplementation of the lower capacity of leucine to stimulate muscle protein synthesis in elderly rats [30], a mixture of antioxidants is included in the nutritional composition.
[0049] Vitamin D3 is present in the composition due to its association with muscle strength and for the reduced incidence of falls and fractures in the elderly with vitamin D supplementation; the minimum recommended dose to reduce the risk of falls is between 700-1000 IU / day of vitamin D (equivalent to 17.5 and 25 pg / day) [31-33]. This dose of vitamin D is achieved with the proposed nutritional composition.
[0050] B vitamins of folic acid, vitamin B6 and vitamin B12 are involved in the homocysteine metabolic pathway, a known risk factor for common diseases in the elderly [34] and are commonly deficient in the elderly [27]. Due to the beneficial effect of folic acid, vitamin B6 and vitamin B12 on decreasing blood levels of homocysteine, these vitamins are present in the nutritional composition.
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Thus, the nutritional composition according to the invention may optionally comprise one or more micronutrients, defined as minerals, trace elements and vitamins, selected from the group of sodium, potassium, chloride, calcium, phosphorus, magnesium, carotenoids , vitamin A, vitamin D3, 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 selected from the group of carotenoids, vitamin A, vitamin B6, vitamin B12, vitamin C, vitamin D3, vitamin E, folic acid, calcium, phosphorus, magnesium, selenium and zinc. Preferably, the nutritional composition according to the invention comprises carotenoids, vitamin A, vitamin D3, vitamin E, vitamin B6, vitamin C, folic acid, vitamin B12, selenium and zinc. Preferably, the nutritional composition according to the invention comprises per 100 kcal 10 to 500 pg of carotenoids, 80 to 140 pg of vitamin A, 8 to 750 pg of vitamin B6, 2 to 25 mg of vitamin C, 0.5 to 25 pg of vitamin D3, 0.5 to 10 mg of vitamin E, 10 to 150 pg of folic acid, 0.05 to 5 pg, in particular 0.07 to 5 pg of vitamin B12, 2.5 to 20 pg of selenium and 0.5 to 2.0 mg of zinc. Medicinal use [0052] The nutritional composition according to the invention can be advantageously used for the prevention or treatment of a disease or health condition that involves muscle deterioration in a mammal, preferably a 30-year-old human or more, more preferably 50 years of age or older, more preferably in an elderly human. Muscle deterioration includes any disease or health condition selected from the sarcopenia group; muscle mass loss related to aging, during or after maintaining body weight, during or after energy restriction, during or after resting at home
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23/52 m, during or after treatment of physical trauma (such as fractures) or during or after weightlessness; insufficient synthesis of muscle protein; muscle breakdown; impaired muscle recovery; muscle damage; muscle proteolysis; muscular atrophy; muscular dystrophy; muscle catabolism; muscle wear; loss of muscle strength; loss of muscle function; loss of physical capacity; loss of physical performance; impaired mobility; fragility; inability; and risk of falling.
[0053] Muscle recovery refers to the structural or functional repair of muscle tissue (cells, fibers, sarcomeres). Muscle damage is the mechanical interruption of the muscle fiber, its membrane or the surrounding connective tissue or tendons. Muscle breakdown refers to the breakdown or loss of muscle tissue quality. Muscle atrophy refers to wear or loss of muscle tissue resulting from illness or disuse. Muscular dystrophy is characterized by progressive muscle weakness and loss of muscle tissue. Muscle wasting is the loss of muscle tissue resulting from illness or lack of use. Physical ability is the ability to perform physical activity. Physical performance is the ability to perform a physical task (for example, balance, walking, strength or endurance) at a desired level. Frailty is a health condition that refers to the collection of symptoms or markers primarily due to aging-related skeletal muscle loss and dysfunction, such as: reduced physical activity, muscle weakness, poor performance, physical weakness, poor resistance, exhaustion, slow walking speed, low muscle strength. In the elderly, frailty will increase the risk of adverse events such as death, disability and institutionalization. Disability refers to the inability to perform physical activity.
[0054] According to an additional modality, the composition
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24/52 nutrition according to the invention can be advantageously used for the dietary control of sarcopenia, age-related loss of muscle mass, strength and function.
[0055] According to an additional embodiment, the nutritional composition according to the invention can be advantageously used for any of the following in a mammal, alone or in combination:
- assist in the reconstruction of muscle mass or muscle strength;
- control sarcopenia;
- stimulate muscle protein synthesis, muscle strength or muscle function;
- sustain greater muscle protein synthesis, muscle strength or muscle function;
- improve or maintain mobility;
- satisfy the needs of a sarcopenic mammal;
- stimulate muscle protein synthesis;
- increase muscle mass or muscle strength;
- improve muscle strength or muscle function; and
- improve physical performance.
[0056] According to one embodiment, said mammal is a human being 30 years of age or older, more preferably 50 years of age or older. More preferably, said mammal is an elderly human being. In this regard, it is suggested that in the context of this patent application an elderly human being is a person 50 years of age or older, in particular 55 years of age or older, more particularly 60 years of age or older, older particularly 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, etc. The most
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25/52 developed in the world accepted the chronological age of 65 as a definition of 'elderly' or older person (associated with the age at which you can start receiving pension benefits), but like many Westernized concepts, this is not adapts well, for example, to the situation in Africa. At the moment, there is no standard numerical criterion for the United Nations (UN), but the range according to the UN is 60+ years old to refer to the oldest population in the western world. The more traditional African definitions of an older or 'elderly' person correlate with the chronological ages of 50 to 65, depending on the scenario, region and country. Dosage [0057] The nutritional composition is administered in the form of 1 to 2 servings daily, each serving comprising between 80 and 200 kcal, preferably approximately 150 kcal. Preferably, the nutritional composition is administered in the form of a daily portion. Using the nutritional composition in a liquid form, the portion can comprise 50 to 250 ml of nutritional composition according to the invention, more preferably 200 ml per serving. Using the 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, more preferably approximately 40 g per serving. [0058] The nutritional composition can be administered in a dosage regimen, which can vary in time and according to the needs of the patient. A typical regimen comprises the administration of 2 servings daily during the treatment period, for example, for approximately 3 months, followed by the administration of one daily serving for prevention or as a maintenance dosage. Preferably, the nutritional composition is administered as a daily portion for prevention or as a dosage
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26/52 maintenance.
Nutritional compositions [0059] The present invention also relates to nutritional compositions with a high protein content and low calorie specific to stimulate the synthesis of muscle protein, in the form of a liquid or a solid.
[0060] According to one embodiment, the invention relates to a liquid nutritional composition, suitable for stimulating muscle protein synthesis, which comprises per 100 ml:
(i) less than approximately 100 kcal of energy, (ii) at least approximately 10 g of proteinaceous matter comprising at least approximately 80% by weight of whey protein, relative to the total proteinaceous matter and comprising at least approximately 11 % by weight of leucine, in relation to total proteinaceous matter, of which at least approximately 20% by weight is in a free form, in relation to total leucine, (iii) a source of fat and a source of digestible carbohydrates and (iv) one or more micronutrients selected from the group of carotenoids, vitamin A, calcium, magnesium, vitamin B6, vitamin C, vitamin D3, vitamin E, folic acid, vitamin B12, selenium and zinc. [0061] Preferably, the liquid nutritional composition according to the invention comprises less than 90 kcal, preferably less than 80 kcal of energy per 100 ml.
[0062] According to an additional embodiment, the invention relates to a liquid nutritional composition that comprises per 100 ml:
(i) approximately 75 kcal of energy, (ii) approximately 10.5 g of proteinaceous matter
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27/52 comprising approximately 10 g of whey protein and comprising approximately 1.4 to approximately 1.5 g of leucine of which approximately 0.4 g is in a free form, (iii) approximately 1.5 g of fat and approximately
4.4 to approximately 4.8 g of digestible carbohydrates, (iv) approximately 0.15 mg of carotenoids, approximately 75 pg of vitamin A, approximately 375 pg of vitamin B6, approximately 1.5 pg of vitamin B12, approximately 16 mg of vitamin C, approximately 10 pg of vitamin D3, approximately 3.8 mg of vitamin E, approximately 100 pg of folic acid, approximately 7.5 pg of selenium, approximately 1.1 mg of zinc and (v) optionally , a source of dietary fiber.
[0063] According to an additional embodiment, the invention relates to a liquid nutritional composition that comprises per 100 ml:
(i) approximately 75 kcal of energy, (ii) approximately 10.5 g of proteinaceous matter comprising approximately 10 g of whey protein and comprising approximately 1.5 g of leucine of which approximately 0.4 g is in a form (iii) approximately 1.5 g of fat and approximately
4.4 g of digestible carbohydrates, (iv) approximately 0.15 mg of carotenoids, approximately 75 pg of vitamin A, approximately 375 pg of vitamin B6, approximately 1.5 pg of vitamin B12, approximately 16 mg of vitamin C, approximately 10 pg of vitamin D3, approximately 3.8 mg of vitamin E, approximately 100 pg of folic acid, approximately 7.5 pg of selenium, approximately 1.1 mg of
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28/52 zinc and (v) optionally, a source of dietary fiber.
[0064] According to an additional embodiment, the invention relates to a liquid nutritional composition that comprises per 100 ml:
(i) approximately 75 kcal of energy, (ii) approximately 10.5 g of proteinaceous matter comprising approximately 10 g of whey protein and comprising approximately 1.4 g of leucine of which approximately 0.4 g is in a form (iii) approximately 1.5 g of fat and approximately
4.4 g of digestible carbohydrates, (iv) approximately 0.15 mg of carotenoids, approximately 75 pg of vitamin A, approximately 375 pg of vitamin B6, approximately 1.5 pg of vitamin B12, approximately 16 mg of vitamin C, approximately 10 pg of vitamin D3, approximately 3.8 mg of vitamin E, approximately 100 pg of folic acid, approximately 7.5 pg of selenium, approximately 1.1 mg of zinc and (v) optionally, a fiber source dietary.
[0065] When a source of dietary fiber is added in the above composition, it is preferable to add a total amount of approximately 0.83 g of dietary fiber per 100 mL comprising 0.63 g of GOS, 0.07 g of FOS / inulin and 0.14 g of low viscosity pectin.
[0066] Said high amounts of whey protein can be achieved using processes of the invention such as those disclosed in WO 2009/113858, the content of which is incorporated herein by reference.
[0067] According to one modality, the nutritional composition
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29/52 is packaged in the form of a 100 to 300 ml portion, more preferably in the form of a 200 ml portion.
[0068] According to one embodiment, the invention relates to a solid nutritional composition, suitable for stimulating the synthesis of muscle protein, which comprises per 100 g of dry weight:
(i) less than 500 kcal of energy, (ii) at least 49 g of proteinaceous matter comprising at least approximately 80% by weight of whey protein, in relation to the total proteinaceous matter and comprising at least approximately 11% by weight leucine weight, relative to total proteinaceous matter, of which at least approximately 20% by weight is in a free form, relative to total leucine, (iii) a source of fat and a source of digestible carbohydrates, ( iv) one or more micronutrients selected from the group of carotenoids, vitamin A, calcium, magnesium, vitamin B6, vitamin C, vitamin D3, vitamin E, folic acid, vitamin B12, selenium and zinc. [0069] The solid nutritional composition according to the invention comprises per 100 g, less than 445 kcal, preferably less than 395 kcal of energy.
[0070] According to one embodiment, the invention relates to a solid nutritional composition, suitable for stimulating muscle protein synthesis, which comprises per 100 g dry weight:
(i) approximately 375 kcal of energy, (ii) approximately 52 to approximately 53 g of proteinaceous matter comprising approximately 50 g of whey protein and comprising approximately 7.2 to approximately 7.5 g of leucine, of which approximately 1.8 to approximately 2 g are in a free form, (iii) approximately 7.5 g of fat and approximately
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30/52 to approximately 24 g of digestible carbohydrates, (iv) approximately 0.75 mg of carotenoids, approximately 376 pg of vitamin A, approximately 1.88 mg of vitamin B6, approximately 80 mg of vitamin C, approximately 50 pg of vitamin D3, approximately 18.8 mg of vitamin E, approximately 500 pg of folic acid, approximately 7.5 pg of vitamin B12, approximately 38 pg of selenium, approximately 5.5 mg of zinc and (v) optionally, a source of dietary fiber.
[0071] According to one embodiment, the invention relates to a solid nutritional composition, suitable for stimulating the synthesis of muscle protein, which comprises per 100 g of dry weight:
(i) approximately 375 kcal of energy, (ii) approximately 52 g of proteinaceous matter which comprises approximately 50 g of whey protein and which comprises approximately 7.5 g of leucine of which approximately 1.9 g is in a form free, (iii) approximately 7.5 g of fat and approximately 23 g of digestible carbohydrates, (iv) approximately 0.75 mg of carotenoids, approximately 376 pg of vitamin A, approximately 1.88 mg of vitamin B6, approximately 80 mg of vitamin C, approximately 50 pg of vitamin D3, approximately 18.8 mg of vitamin E, approximately 500 pg of folic acid, approximately 7.5 pg of vitamin B12, approximately 38 pg of selenium, approximately 5.5 mg zinc and, (v) optionally, a source of dietary fiber.
[0072] According to one embodiment, the invention relates to a solid nutritional composition, suitable for stimulating the synthesis of
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31/52 muscle protein, which comprises per 100 g dry weight:
(i) approximately 375 kcal of energy, (ii) approximately 52 g of proteinaceous matter which comprises approximately 50 g of whey protein and which comprises approximately 7.2 g of leucine of which approximately 2 g is in a free form, (iii) approximately 7.5 g of fat and approximately 23 g of digestible carbohydrates, (iv) approximately 0.75 mg of carotenoids, approximately 376 pg of vitamin A, approximately 1.88 mg of vitamin B6, approximately 80 mg of vitamin C, approximately 50 pg of vitamin D3, approximately 18.8 mg of vitamin E, approximately 500 pg of folic acid, approximately 7.5 pg of vitamin B12, approximately 38 pg of selenium, approximately 5.5 mg of zinc and, (v) optionally, a source of dietary fiber.
[0073] When a source of dietary fiber is added in the above composition, it is preferable to add a total amount of 4.13 g of dietary fiber comprising approximately 3.1 g of GOS, 0.34 g of FOS / inulin and 0.69 g of low viscosity pectin per 100 g dry weight.
[0074] Preferably, the solid nutritional composition according to the invention is formed in the form of a powder, capable of being dissolved in an aqueous solution.
[0075] Preferably, the solid nutritional composition according to the invention is presented in the form of a portion of approximately 20 to 70 g, more preferably of approximately 40 g.
[0076] The powder can be presented in the form of a sachet, a cup and the like, having the size of approximately the size of
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32/52 a portion or may be presented in a container, comprising several portions, such as 7 to 25 portions, for example, 10 to 25 portions, optionally accompanied with a measuring device such as a spoon.
[0077] Regarding both the liquid and solid nutritional composition according to the invention, one or more of the following specifications apply:
- the amount of fat can vary between 10 and 35 en%, preferably between 15 and 30 en%;
- the amount of carbohydrate can vary between 10 and 35 en%, preferably between 15 and 30 en%;
- the relative amounts of the sum of fat and carbohydrate vary between 10 and 60 en%, for example, between 30 and 60 en%;
the proteinaceous matter comprises at least approximately 85% by weight of whey protein, preferably at least approximately 90% by weight and more preferably approximately 95% by weight of whey protein.
- the proteinaceous material comprises at least 45% by weight, preferably at least 47% by weight and more preferably at least approximately 50% by weight of essential amino acids (EAA).
the proteinaceous matter comprises at least approximately 12% by weight, preferably at least approximately 12.5% by weight, more preferably at least approximately 13% by weight of leucine.
- the proteinaceous material comprises at least approximately 22.5% by weight, preferably at least approximately 26% by weight of leucine in a free form, in relation to the amount of total leucine.
- proteinaceous matter comprises total leucine, valine to
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33/52 such and total isoleucine in a leucine: valine: total isoleucine ratio of approximately 1.7-3: 1: 1.
- the nutritional composition further comprises one or more dietary fibers selected from the group of short-chain GOS, long-chain FOS, inulin and low-viscosity pectin.
[0078] The compositions according to the invention can be prepared using methods known to those skilled in the art, in particular as disclosed in WO 2009/113858, which is incorporated herein by reference in its entirety. Powders can be produced by methods commonly known in the art to the person skilled in the art, such as spray drying the liquid composition or dry mixing powdered ingredients or a combination of both.
[0079] The invention will now be further elucidated by several examples, without being limited or linked to them.
DESCRIPTION OF THE FIGURES [0080] Figure 1: Time curves for average serum leucine concentrations.
[0081] Figure 2: Time curves for average total concentrations of essential amino acids in serum.
[0082] Figure 3: Time curves for average total serum amino acid concentration.
[0083] Figure 4: Schematic diagram of a clinical study. EXPERIMENTAL
1. CLINICAL STUDY [0084] A clinical study was carried out with the objective of evaluating the acute effect of the protein source and the caloric density of the oral nutritional composition with high protein content on this serum amino acid levels in the elderly. For this, a whey protein (21 g) with a high protein content, rich in leucine (3 g), a low-calorie composition (composition according to the invention) was compared
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34/52
- Active) with an oral nutritional composition isonitrogenated with casein-protein (Control 1, low caloric) or with high caloric density (Control 2, casein-protein; Control 3, whey protein-protein). A randomized, controlled, blinded design, crossed over 12 healthy elderly subjects (5 male, 7 female), recruited from a database of volunteers at a clinical research unit in the Netherlands as used. The subjects were between 65 and 70 years of age and had normal weight or slightly overweight (Body Mass Index (BMI) in the range of 21.7 - 29.7 kg / m ² ). Statistics were performed using a mixed model analysis of variance with random effect for subjects, fixed effect for protein source (2 levels: whey protein, casein) and caloric density (2 levels: low, high) and fixed interaction of protein source * caloric density. The statistical model included serum albumin, serum C-reactive protein (CRP) and concentration of result parameter in baseline serum as covariates. Additional analyzes were performed on the maximum concentration of leucine in serum (Leumax), which uses age, level of physical activity, sex or BMI (categories <25 and> 25 kg / m ² ) as an additional covariate. Bilateral tests were used with α = 0.05.
[0085] Leumax was significantly higher for Active compared to Control 1 (521 vs. 260 pmoles / L, p <0.001). The protein source effect was similar for high calorie products; Leumax was significantly higher for Control 3 compared to Control 2 (406 vs. 228 pmoles / L, p <0.001). Intake of low-calorie products led to Leumax significantly higher compared to high-calorie products (p <0.001 for pooled analyzes). The protein source effect was strongest for low-calorie products (p <0.001 for interaction effect). These effects (of protein source, caloric density and interaction) were also presented for
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35/52 maximum total serum essential amino acid concentration (EAAmax) and maximum total serum amino acid concentration (AAmax). The protein source and caloric density also affected the incremental area under the curve (iAUC) for 4 hours after ingesting the leucine product (44,588 pmoles / L * min [Active] vs. 22,207 pmoles / L * min [Control 1 ], p <0.001; 35.952 pmoles / L * min [Control 3] vs. 15.793 pmoles / L * min [Control 2], p <0.001 and p <0.001 for pooled analysis of low-calorie vs. high-calorie products). The same effects were presented for iAUC EAA and iAUC AA. The time required to achieve half the iAUC (t /) for leucine was significantly shorter for Active compared to Control 1 (87 vs. 119 min, p <0.001) and was significantly shorter for Control 3 compared to Control 2 (101 vs. 118 min, p = 0.003). The effect of the protein source on t / has also been discovered for EAA and AA. The maximum concentration of insulin in the serum did not differ between Active and Control 1 (p = 0.915), nor between Control 3 and Control 2 (p = 0.989). There was no interaction effect between protein source and caloric density for maximum serum insulin concentration (p = 0.933). The absence of a protein source effect and the interaction effect has also been discovered for serum insulin iAUC. The maximum concentration of glucose in serum was significantly lower for Active compared to Control 1: 5.54 vs. 6.05 mmoles / L (p = 0.013). The protein source effect was absent for high calorie products (Control 3 [6.42 mmoles / L] vs. Control 2 [6.66 mmoles / L], p = 0.195). There was no interaction effect between the protein source and the caloric density for the maximum concentration of glucose in the serum (p = 0.314). The protein source effect and the interaction effect were absent for serum glucose iAUC. The effect of caloric density was shown for maximum concentration and iAUC, both for insulin and glucose, with lower values for
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36/52 low calorie (all values of p <0.001 for grouped analyzes). There were no clinically relevant differences in adverse events or GI symptoms observed. Vital signs and profiles of valine and isoleucine in the serum do not lead to safety concerns. Active was associated with less satiety than Control 1; especially the hunger was greater, for 4 hours after eating.
[0086] This study confirmed that whey protein is a faster source of amino acids than casein protein, resulting in higher levels of amino acids in serum. Surprisingly, the low calorie density also confirms the protein source effect on amino acid levels. The combination of whey protein and low caloric density provided the most pronounced effect on the maximum leucine concentration. Therefore, the Active product is preferred to cause muscle protein synthesis; at least for casein products and probably also for a high calorie equivalent. No clinically relevant differences in insulin and glucose levels were observed between products containing whey protein and casein. There were no safety concerns related to the consumption of 1 dose of any of the study products. The clinical study demonstrated that the composition (150 kcal in the clinical study) resulted in higher blood levels (maximum / peak level and iAUC) of leucine, essential amino acids and total amino acids compared to a similar protein composition at 320 kcal (approximately 26 en % protein). The composition results in higher and faster blood levels (maximum / peak level and iAUC) of leucine, essential amino acids and total amino acids compared to a proteinaceous composition that contains 100% slow casein protein, either as 150 kcal or 320 kcal.
[0087] These data suggest that biological availability (peri
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37/52 ferric) of anabolic amino acids (leucine and essential amino acids) is great with the composition comprising whey protein as the source of proteins in a formulation that contains low calories (partly originating from fat and CHO). As it is known from the literature that the levels of leucine and essential amino acids in the blood are positively related to the protein synthesis stimulus in the muscle, it is anticipated that the muscle protein synthesis stimulus is optimal with the proposed nutritional composition.
Details
Subjects and Methods
Subjects [0088] 12 healthy elderly subjects (5 males, 7 females; aged between 65 and 70 years BMI range 21.7 - 29.7 kg / m ² ) participated in this randomized, controlled, blinded, crossed. Subjects with knowledge or suspicion of Diabetes Mellitus (glucose concentration> 7.0 mmoles / L) were excluded from the study. In addition, subjects were excluded in the case of any (history of) gastrointestinal disease that interferes with gastrointestinal function, notable allergy to milk and milk products or galactosemia, current or recent (within the last three months) with perforation, current infection or fever in the last 7 days at the discretion of the doctor, use of antibiotics within 3 weeks of the start of the study, current use of corticosteroids, hormones, antacids or any medication that would influence the production of gastric acid, a requirement for any nutritional reinforcement or adherence to any specific diet (for example, for weight loss, vegetarian).
[0089] All subjects signed an informed consent form and were randomly assigned to receive a single order of the 4 study products. The study products were: 1) The
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38/52 product according to the invention: Active: high whey protein content of milk-leucine, 150 kcal; 2) Control 1: high casein content, 150 kcal; 3) Control 2: high casein content, 320 kcal; 4) Control 3: high protein content of whey-leucine, 320 kcal (Table 1). Each study product was administered as a cake (consumed within 5 minutes) in a liquid formulation.
Table 1. Nutritional composition of the study products
Nutrients unity Active Control 1 Control 2 Control 3 High whey content / Leu 150kcal High Casein content 150kcal High Casein content 320kcal High whey content / High Leu 320kcal Energy kcal 150 150 320 320 Protein g 21 21 21 21 - intact whey g 20 - - 20 - casein g - 21 21 - - Leucine (total) g 3 2 2 3 - EAA (total)10 9 9 10 Carbohydrate g 10.5 10.1 32.0 32.9 Fat _ 3 3 12 12
Experimental protocol [0090] The subjects visited the site for research in a fasted state on 4 separate mornings. After ingesting the study product, the subjects remained in place for 4 hours to undergo study evaluations. Consultations were at least 1 week apart (7-10 days after the previous consultation). Figure 4 presents a schematic diagram of the study.
[0091] In each consultation, the subjects were asked about intercurrent illnesses, intercurrent use of medication and nutritional supplements and intake of diet and physical activities during the last 24 hours. If the subjects a) experienced an infection or a fever during the last 7 days, b) used antibiotics, corticosteroids, hormones, antacids or any medication that influenced gastric acid production or c) if they were not in one
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39/52 fasting state ₃ the appointment was rescheduled.
[0092] The protocol at each visit was identical and included: GI tolerance was assessed at baseline (-30 min), blood pressure (BP) and heart rate (HR) at t = -20 min. A flexible cannula for drawing blood was placed in a vein in the forearm for drawing a blood sample. The study product was consumed (T0) and blood samples (5 ml) were taken during the entire 4-hour study period: 2 samples at = -15 min and the other 13 samples at =: 0 min (before ingestion) product), 15 min, 30 min, 45 min, 1 h, 1 h 15 min, 1 h 30 min, 1 h 45 min, 2 h, 2 h 30 min, 3 h, 3 h 30 min and 4 hours. Blood samples were taken with the subject in a sitting position. Blood pressure, heart rate and GI tolerance were measured again at t = 4 h.
Sample analysis [0093] The blood was centrifuged to obtain serum, which was subsequently stored at -20 degrees Celsius until analysis. Serum concentrations of 21 amino acids (leucine, isoleucine, valine, histidine, lysine, methionine, phenylalanine, threonine, tryptophan, alanine, arginine, asparagines, aspartic acid, citrulline, cysteine, glutamic acid, glutamine, glycine, serine, taurine and tyrosine) were analyzed for all time points, using HPLC, as is well known to the person skilled in the art. The concentrations of the 9 essential amino acids: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine are added (EAA). The concentrations of all 21 amino acids are added (AA).
Statistical analysis [0094] All dependent variables were analyzed using a mixed model with a disorderly effect for subjects, a fixed effect for the factors protein (2 levels: whey protein, casein) and caloric density (2 levels: low, high) and an interaction
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Fixed 40/52 protein calorie density *. In separate analyzes, to analyze the differences between treatments, the difference between the Active and Control 1 product was analyzed, as well as Active vs. Control 3 and Control 1 vs. Control 2.
Results
Serum Leucine [0095] The time curves for mean serum leucine concentration are shown in figure 1.
[0096] The maximum leucine concentration in serum was significantly higher in Active than in Control 1: 521 vs. 260 pmoles / L (p <0.001).
[0097] This difference between whey protein + leucine vs. casein for low-calorie products was, to a lesser extent, also observed for high-calorie products (Control 3 [406 pmoles / L] vs. Control 2 [228 pmoles / L], p <0.001).
[0098] Pooled analyzes of low-calorie products vs. high-calorie products (Active and Control 1 vs. Control 2 and Control 3) showed significantly higher Leumax for low calorie density (p <0.001). This effect was stronger for products rich in leucine with high whey protein (Active vs. Control 3, p <0.001), than for products with a high casein protein content (Control 1 and Control 2, p = 0.042 ), reflected by the significant interaction effect between the protein source and caloric density (p <0.001).
[0099] iAUC Leu was significantly higher in Active than in Control 1: 44588 vs. 22207 pmoles / L * min (p <0.001). This difference between whey protein + leucine vs. casein for low-calorie products was also observed for high-calorie products (Control 3 [35952 pmoles / L * min] vs. Control 2 [15793 pmoles / L * min], p <0.001). Pooled analysis of low-calorie products
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41/52 vs. high-calorie products showed significantly higher iAUC Leu for low calorie density (p <0.001). There was no significant interaction effect between the protein source and caloric density for iAUC Leu (p = 0.286).
[00100] t / Leu was significantly lower in Active than in Control 1: 87 vs. 119 min (p <0.001). The difference between whey protein + leucine vs. casein was also observed for high-calorie products (Control 3 [101 minutes] vs. Control 2 [118 min], p = 0.003). There was no significant difference between low and high caloric density (p = 0.100). There was a tendency for the interaction effect between protein source and caloric density (p = 0.074).
Essential Amino Acids in Serum (EAA) [00101] The time curves for the average total concentration of essential amino acid in serum are shown in figure 2.
[00102] The total concentration of essential amino acid in the serum in the baseline (EA Baseline) was at a similar level for all products (860 - 890 μ moles / L). The baseline was included as a covariate in the statistical model.
[00103] The maximum concentration of essential amino acid in serum (EAAmax) was significantly higher in Active than in Control 1: 2187 vs. 1540 pmoles / L (p <0.001). This difference between whey protein + leucine vs. casein for low-calorie products was, to a lesser extent, also observed for high-calorie products (Control 3 [1792 pmoles / L] vs. Control 2 [1420 pmoles / L], p <0.001).
[00104] The grouped analysis of low calorie products vs. high calorie products showed significantly higher EAAmax for low calorie density (p <0.001). This effect was stronger for products rich in leucine with high whey protein (Active vs. Control 3, p <0.001), than for products with high protein content.
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42/52 high casein theine (Control 1 and Control 2, p = 0.023), reflected by the effect of significant interaction between the protein source and caloric density (p <0.001).
[00105] iAUC EAA was significantly higher in Active than in Control 1: 129793 vs. 100516 pmoles / L * min (p <0.001). This difference between whey protein + leucine vs. casein for low-calorie products was also observed for high-calorie products (Control 3 [101181 pmoles / L * min] vs. Control 2 [75181 pmoles / L * min], p <0.001). The grouped analysis of low-calorie products vs. high calorie products showed significantly higher iAUC EAA for low calorie density (p <0.001). There was no significant interaction effect between the protein source and the caloric density for iAUC EAA (p = 0.673).
[00106] t / EAA was significantly lower in Active than in Control 1: 83 vs. 115 min (p <0.001). The difference between whey protein + leucine vs. casein was also observed for high-calorie products (Control 3 [94 min] vs. Control 2 [117 min], p <0.001). There was a trend towards an effect of caloric density on t / EAA (p = 0.093). The interaction effect between the protein source and caloric density was absent (p = 0.223).
Total Amino Acids (AA) [00107] The time curves for average total serum amino acid concentration are shown in figure 3.
[00108] The total serum amino acid concentration in the baseline (AA baseline) was similar for all products (2780 - 2880 μmol / L). The baseline was included as a covariant in the statistical model.
[00109] The maximum serum amino acid concentration (AAmax) was significantly higher in Active than in Control 1: 4687 vs. 3946 μmol / L (p <0.001). This difference between whey protein +
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43/52 leucine vs. casein for low-calorie products was also observed for high-calorie products (Control 3 [4141 μ mol / L] vs. Control 2 [3699 μmol / L], p <0.001).
[00110] Analysis of groups of low-calorie products vs. high calorie showed significantly higher AAmax for low calorie density (p <0.001). This effect was stronger for products rich in leucine with high whey protein (Active vs. Control 3, p <0.001), than for products with a high casein protein content (Control 1 and Control 2, p = 0.003), reflected by the effect of significant interaction between protein source and caloric density (p = 0.015).
[00111] iAUC AA was significantly higher in Active than in Control 1: 162702 vs. 143018 μ mol / L * min (p = 0.032). This difference between whey protein + leucine vs. casein for low-calorie products was also observed for high-calorie products (Control 3 [128047 μmol / L * min] vs. Control 2 [105525 μmol / L * min], p = 0.008). Analysis of groups of low-calorie products vs. high-calorie exhibited significantly higher iAUC AA for low-calorie density (p <0.001). There is no significant interaction effect between the protein source and caloric density for iAUC AA (p = 0.819).
[00112] t / AA was significantly lower in Active than in Control 1:78 vs. 101 min (p <0.001). The difference between whey protein + leucine vs. casein was also observed for high-calorie products (Control 3 [87 min] vs. Control 2 [103 min], p = 0.007). There was no significant difference between low and high caloric density (p = 0.199). The interaction effect between the protein source and the caloric density for t / AA was absent (p = 0.413).
Conclusion [00113] The concentration of leucine in the serum increased up to above 500 μmols / L after ingesting the low-calorie product rich in leuci
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44/52 na with high whey protein. The difference in Leumax with the low-calorie product with a high casein content (520 vs. 260 qmol / L) was greater than expected. The a priori assumption about the intervention effect was a difference of 100 qmol / L in Leumax between Active and Control 1, estimated from Dangin and others. [15]. The serum EAA concentrations were also higher after ingestion of the low-calorie product rich in leucine with high whey protein compared to the low-calorie product with a high casein content.
[00114] This study confirmed that whey protein is a faster source of amino acids than casein protein, which is considered a slow protein [7]. The rate of appearance of amino acids in the circulation was much higher, reflected by the time until half of the iAUC. t / was shorter for leucine-rich products with high whey protein; not only for leucine and total essential amino acids, but also for total amino acids. The time curves for individual amino acids, other than leucine, confirmed this.
[00115] The high leucine peak for products rich in leucine with high whey protein was more pronounced for the low calorie product. Leumax values for high calorie products were 406 (rich in leucine with high whey protein) and 228 (high casein protein) qmol / L. Leucine concentrations above 300 qmol / L appeared to be efficient in stimulating muscle protein synthesis in the elderly [35] [infusion of amino acids]; [36] [leucine supplemented nutrition]). Although there are no evident data on the dose-response relationship between serum leucine and muscle protein synthesis, the hypothesis was raised that the product rich in leucine with low-calorie high whey protein is the preferred product to stimulate muscle protein synthesis.
2. NUTRITIONAL COMPOSITIONS
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45/52 [00116] The following nutritional compositions according to the invention are suitable for the prevention or treatment of a disease or state of health in a mammal, for example, an elderly mammal, which involves protein synthesis muscular.
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Ingredient Most preferred per 100 kcal Liquid fed by sips I (per 100 mL) Liquid fed by sips II (per 100 mL) Liquid fed by sips III (per 100 mL) Powder I (per 100 g) Powder II (per 100 g) Powder III (per 100 g) Energy (kcal) 100 75 75 75 375 375 375 protein (En%) 55 56 55 55 56 55 55 fat (En%) 18 18 18 18 18 18 18 carbs that can be digested (En%) 25 23 24 24 23 25 25 carbs that cannot be digested (En%) 2 3 3 3 3 2 2 Total protein (g) 14.0 10.5 10.5 10.5 52.7 51.9 51.9 Intact whey protein (g) 13.3 10.0 10 10 50.0 49.1 49.1 (% by weight of p.m.) (95% (95% in (95% (95% (95% (95% (95%by weight) Weight) by weight) by weight) by weight) by weight) by weight) Free leucine (g) 0.5 0.4 0.4 0.4 2.0 1.8 1.9 (% by weight of total Leu) (26% (26% (26% (26% (26% (26% (26%by weight) by weight) by weight) by weight) by weight) by weight) by weight) Total leucine (g) 2.0 1.5 1.4 1.5 7.5 7.2 7.5 (% by weight of p.m.) (14% (14% (14% (14% (14% (14% (14%by weight) by weight) by weight) by weight) by weight) by weight) by weight) Total isoleucine (g) 1.0 0.75 0.7 0.7 3.75 3.5 3.5 Total valine (g) 1.0 0.75 0.7 0.7 3.75 3.5 3.5
46/52
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Ingredient Most preferred per 100 kcal Liquid fed by sips I (per 100 mL) Liquid fed by sips II (per 100 mL) Liquid fed by sips III (per 100 mL) Powder I (per 100 g) Powder II (per 100 g) Powder III (per 100 g) EAA (g)(% by weight of p.m.) 7.0 (50% by weight) 5.3 (50% by weight) 5.3 (50% by weight) 5.3 (50% by weight) 26.4 (50% by weight) 26 (50% by weight) 26 (50% by weight) Fat (g) 2.0 1.5 1.5 1.5 7.5 7.5 7.5 Digestable carbohydrates (g) 6.4 4.8 4.4 4.4 23.9 23.1 23.1 Carbs that cannot be eaten (g) 1.11 0.84 0.98 0.98 4.17 4.17 4.17 GOS (g) 0.83 0.63 0.63 0.63 3.13 3.13 3.13 FOS / inulin (g) 0.09 0.07 0.07 0.07 0.35 0.35 0.35 Low viscosity pectin (g) 0.19 0.14 0.14 0.14 0.69 0.69 0.69 Zinc (mg) 1.5 1.1 1.1 1.1 5.5 5.5 5.5 Selenium (pg) 10 7.5 7.5 7.5 37.5 38 38 Carotenoids (pg) 200 150 150 150 750 750 750 Vitamin C (mg) 21.3 16.0 16.0 16.0 80.0 80.0 80.0
47/52
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Ingredient Most preferred per 100 kcal Liquid fed by sips I (per 100 mL) Liquid fed by sips II (per 100 mL) Liquid fed by sips III (per 100 mL) Powder I (per 100 g) Powder II (per 100 g) Powder III (per 100 g) Vitamin E (mg-a-TE) 5.0 3.8 3.8 3.8 18.8 19 19 Vitamin D3 ^ g) 13.3 10.0 10.0 10.0 50.0 50.0 50.0 Vitamin B6 ^ g) 500 375 375 375 1875 1882 1882 Folic acid (pg) 133 100 100 100 500 501 501 Vitamin B12 (pg) 2.0 1.5 1.5 1.5 7.5 7.5 7.5 Vitamin A (pg) 100 75 75 75 375 376 376 Serving size - 200 mL 200 mL 200 mL 40 g 40 g 40 g
48/52
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49/52
BIBLIOGRAPHIC REFERENCES
1. Rolland, Y. et al., Sarcopenia: its assessment, etiology, pathogenesis, consequences and future perspectives. J Nutr Health Aging, 2008. 12 (7): p. 433-50.
2. Short, K.R. and K.S. Nair, Mechanisms of sarcopenia of aging. J Endocrinol Invest, 1999. 22 (5 Suppl): p. 95-105.
3. Boirie, Y., Physiopathological mechanism of sarcopenia. J Nutr Health Aging, 2009. 13 (8): p. 717-23.
4. Guillet, C. et al., Impaired anabolic response of muscle protein synthesis is associated with S6K1 dysregulation in elderly humans. Faseb J, 2004. 18 (13): p. 1586-7.
5. Rasmussen, B.B. and others, Insulin resistance of muscle protein metabolism in aging. Faseb J, 2006. 20 (6): p. 768-9.
6. Cuthbertson, D. et al., Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. Faseb J, 2005. 19 (3): p. 422-4.
7. Boirie, Y. et al., Slow and fast dietary proteins differently modulate postprandial protein accretion. Proc Natl Acad Sci U SA, 1997. 94 (26): p. 14930-5.
8. Katsanos, C.S. et al., A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly. Am J Physiol Endocrinol Metab, 2006. 291 (2): p. E381-7.
9. Volpi, E. et al., Essential amino acids are primarily responsible for the amino acid stimulation of muscle protein anabolism in healthy elderly adults. Am J Clin Nutr, 2003. 78 (2): p. 250-8.
10. Paddon-Jones, D. et al., Differential stimulation of muscle protein synthesis in elderly humans following isocaloric ingestion of amino acids or whey protein. Exp Gerontol, 2006. 41 (2): p. 215-
9.
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11. Katsanos, C.S. et al., Aging is associated with diminished accretion of muscle proteins after the ingestion of a small bolus of essential amino acids. Am J Clin Nutr, 2005. 82 (5): p. 1065-73.
12. Paddon-Jones, D. et al., Amino acid ingestion improves muscle protein synthesis in the young and elderly. Am J Physiol Endocrinol Metab, 2004. 286 (3): p. E321-8.
13. Anthony, J.C. et al., Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycinsensitive pathway. J Nutr, 2000. 130 (10): p. 2413-9.
14. Rieu, I. et al., Increased availability of leucine with leucine-rich whey proteins improves postprandial muscle protein synthesis in aging rats. Nutrition, 2007. 23 (4): p. 323-31.
15. Dangin, M. et al., The rate of protein digestion affects protein gain differently during aging in humans. J Physiol, 2003. 549 (Pt 2): p. 635-44.
16. Bohe, J. et al., Human muscle protein synthesis is modulated by extracellular, not intramuscular amino acid availability: a dose-response study. J Physiol, 2003. 552 (Pt 1): p. 315-24.
17. Wolfe, R.R., Protein supplements and exercise. Am J Clin Nutr, 2000. 72 (2 Suppl): p. 551S-7S.
18. Marieb, E.N., Human anatomy & Physiology. 4th ed. 1998, Menlo Park, California: Benjamin / Cummings Science Publishing. 1192.
19. Dangin, M. et al., Influence of the protein digestion rate on protein turnover in young and elderly subjects. J Nutr, 2002. 132 (10): p. 3228S-33S.
20. Dangin, M. et al., The digestion rate of protein is an independent regulating factor of postprandial protein retention. Am J Physiol Endocrinol Metab, 2001.280 (2): p. E340-8.
21. Boirie, Y., P. Gachon and B. Beaufrere, Splanchnic and whole-body leucine kinetics in young and elderly men. Am J Clin Nutr,
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1997. 65 (2): p. 489-95.
22. Volpi, E. et al., Oral amino acids stimulate muscle protein anabolism in the elderly despite higher first-pass splanchnic extraction. Am J Physiol, 1999. 277 (3 Pt 1): p. E513-20.
23. Clarkston, W.K. and others, Evidence for the anorexia of aging: gastrointestinal transit and hunger in healthy elderly vs. young adults. Am J Physiol, 1997. 272 (1 Pt 2): p. R243-8.
24. WHO, Keep fit for life: meeting the nutritional needs of older persons. 2002.
25. Holick, M.F., Vitamin D deficiency. N Engl J Med, 2007. 357 (3): p. 266-81.
26. Lesser, S. et al., Nutritional situation of the elderly in Eastern / Baltic and Central / Western Europe - the AgeingNutrition project. Ann Nutr Metab, 2008. 52 Suppl 1: p. 62-71.
27. Raats, M.L., L. de Groot, and W. van Staveren, Food for the aging population. 2009, Cambridge, England: Woodhead Publishing Limited.
28. Bartali, B. et al., Low nutrient intake is an essential component of frailty in older persons. J Gerontol A Biol Sci Med Sci, 2006. 61 (6): p. 589-93.
29. Semba, R.D. and others, Low serum micronutrient concentrations predict frailty among older women living in the community. J Gerontol A Biol Sci Med Sci, 2006. 61 (6): p. 594-9.
30. Marzani, B. et al., Antioxidant supplementation restores defective leucine stimulation of protein synthesis in skeletal muscle from old rats. J Nutr, 2008. 138 (11): p. 2205-11.
31. Bischoff-Ferrari, H.A. and others, Higher 25hydroxyvitamin D concentrations are associated with better lowerextremity function in both active and inactive persons aged> or = 60 y. Am J Clin Nutr, 2004. 80 (3): p. 752-8.
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32. Bischoff-Ferrari, H.A. et al., Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a metaanalysis of randomized controlled trials. Arch Intern Med, 2009. 169 (6): p. 551-61.
33. Bischoff-Ferrari, H.A. and others, Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomized controlled trials. Bmj, 2009. 339: p. b3692.
34. Seshadri, S. et al., Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med, 2002. 346 (7): p. 476-83.
35. Volpi, E. et al., Exogenous amino acids stimulate net muscle protein synthesis in the elderly. J Clin Invest, 1998. 101 (9): p. 2000-7.
36. Rieu, I. et al., Leucine supplementation improves muscle protein synthesis in elderly men independently of hyperaminoacidaemia. J Physiol, 2006. 575 (Pt 1): p. 305-15.

权利要求:
Claims (24)
[1]
1. Nutritional composition comprising 100 kcal:
(i) proteinaceous matter comprising at least approximately 11% by weight of leucine, relative to the total proteinaceous matter, of which at least approximately 20% by weight is in a free form, in relation to the total leucine, (ii) a source of fat and a source of digestible carbohydrates, characterized by the fact that the composition comprises at least approximately 12 g of proteinaceous matter which comprises at least approximately 80% by weight of whey protein, in relation to the total proteinaceous matter , and the composition being a portion comprising between 80 and 200 kcal, the term approximately meaning deviation of 5% or less from the value provided.
[2]
2. Composition according to claim 1, characterized by the fact that proteinaceous matter comprises at least
12.5 g of proteinaceous matter per 100 kcal.
[3]
Composition according to claim 1 or 2, characterized in that the proteinaceous material comprises at least 85% by weight of whey protein.
[4]
Composition according to any one of claims 1 to 3, characterized in that the proteinaceous material comprises at least 45% by weight of essential amino acids (EAA).
[5]
Composition according to any one of claims 1 to 4, characterized in that the proteinaceous material comprises at least 12% by weight of leucine.
[6]
6. Composition according to any of the claims
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2/6 cations 1 to 5, characterized by the fact that the total leucine comprises at least 22.5% by weight of leucine in a free form, in relation to the total amount of leucine.
[7]
Composition according to any one of claims 1 to 6, characterized in that the proteinaceous material comprises a total amount of leucine, valine and isoleucine in a leucine: valine: isoleucine ratio of approximately 1.73: 1: 1, the term approximately meaning a deviation of 5% or less from the value provided.
[8]
8. Composition according to any one of claims 1 to 7, characterized in that the nutritional composition further comprises one or more dietary fibers selected from the group of short-chain GOS, long-chain FOS, inulin and low-viscosity pectin .
[9]
9. Composition according to any one of claims 1 to 8, characterized in that the nutritional composition further comprises carotenoids, vitamin A, vitamin B6, vitamin C, vitamin D3, vitamin E, folic acid, vitamin B12, selenium and zinc.
[10]
10. Composition, according to claim 1, characterized by the fact that it comprises per 100 kcal:
(ii) approximately 14 g of proteinaceous matter which comprises approximately 95% by weight of whey protein, in relation to the total proteinaceous matter and which comprises at least approximately 14% by weight of leucine, in relation to the total proteinaceous matter, of which at least approximately 26% by weight are in a free form, relative to total leucine, (iii) approximately 2 g of fat and approximately
6.2 g of digestible carbohydrates, the term approximately meaning deviation from
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3/6
5% or less of the value provided, each portion comprising approximately 150 kcal.
[11]
11. Nutritional composition comprising:
a proteinaceous matter comprising at least approximately 11% by weight of leucine, relative to the total proteinaceous matter, of which at least approximately 20% by weight is in a free form, in relation to total leucine, a source of fat and a source of carbohydrates that can be digested, characterized by the fact that the composition is a liquid that comprises per 100 mL:
less than 100 kcal of energy, at least approximately 10 g of the proteinaceous matter, the proteinaceous matter comprising at least approximately 80% by weight of whey protein, relative to the total proteinaceous matter and that the composition comprises one or more selected micronutrients the group of carotenoids, vitamin A, calcium, magnesium, vitamin B6, vitamin D3, vitamin C, vitamin E, folic acid, vitamin B12, selenium and zinc;
the term approximately means a deviation of 5% or less from the value provided.
[12]
12. Liquid nutritional composition according to claim 11, characterized by the fact that it comprises per 100 mL, less than 90 kcal of energy.
[13]
13. Liquid nutritional composition according to claim 11 or 12, characterized by the fact that it comprises per 100 ml:
(i) approximately 75 kcal of energy, (ii) approximately 10.5 g of proteinaceous matter that
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4/6 comprises approximately 10 g of whey protein and comprises approximately 1.5 g of leucine of which approximately 0.4 g is in a free form, (iii) approximately 1.5 g of fat and approximately
4.4 g of digestible carbohydrates, (iv) approximately 0.15 mg of carotenoids, approximately 75 pg of vitamin A, approximately 375 pg of vitamin B6, approximately 1.5 pg of vitamin B12, approximately 16 mg of vitamin C, approximately 10 pg of vitamin D3, approximately 3.8 mg of vitamin E, approximately 100 pg of folic acid, approximately 7.5 pg of selenium, approximately 1.1 mg of zinc, and the term approximately means deviation from 5% or less of the value provided.
[14]
14. Liquid nutritional composition according to claim 13, characterized by the fact that it comprises a source of dietary fiber.
[15]
15. Liquid nutritional composition according to any one of claims 11 to 14, characterized in that it is packaged in the form of a 200 ml portion.
[16]
16. Solid nutritional composition, comprising per 100 g dry weight:
(i) less than 500 kcal of energy, (ii) a source of fat and a source of digestible carbohydrates, the composition of which comprises, (iii) at least 49 g of proteinaceous matter comprising at least approximately 80% by weight of whey protein, in relation to the total proteinaceous matter and which comprises at least approximately 11% by weight of leucine, in relation to the
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5/6 total proteinaceous matter, of which at least approximately 20% by weight is in a free form, in relation to total leucine, (iv) one or more micronutrients selected from the group of carotenoids, vitamin A, calcium, magnesium, vitamin B6 , vitamin C, vitamin D3, vitamin E, folic acid, vitamin B12, selenium and zinc, the term approximately meaning deviation of 5% or less from the value provided.
[17]
17. Solid nutritional composition according to claim 16, characterized by the fact that it comprises per 100 g, less than 445 kcal.
[18]
18. Solid nutritional composition according to claim 16 or 17, characterized by the fact that it comprises per 100 g dry weight:
(i) approximately 375 kcal of energy, (ii) approximately 52 g of proteinaceous matter comprising approximately 50 g of whey protein and comprising approximately 7.5 g of leucine of which approximately 1.9 g is in a form free, (iii) approximately 7.5 g of fat and approximately 23 g of digestible carbohydrates, (iv) approximately 0.75 mg of carotenoids, approximately 376 pg of vitamin A, approximately 1.88 mg of vitamin B6, approximately 80 mg of vitamin C, approximately 50 pg of vitamin D3, approximately 18.8 mg of vitamin E, approximately 500 pg of folic acid, approximately 7.5 pg of vitamin B12, approximately 38 pg of selenium and approximately 5.5 mg zinc, and the term approximately means a deviation of 5% or less from the value provided.
[19]
19. Solid nutritional composition, according to the claim
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6/6 dication 18, characterized by the fact that it comprises a source of dietary fiber.
[20]
20. Solid nutritional composition according to any one of claims 16 to 19, characterized in that it is formed in the form of a powder capable of being dissolved in an aqueous solution.
[21]
21. Solid nutritional composition according to any one of claims 16 to 20, characterized by the fact that it is presented in the form of a portion of approximately 40 g, the term approximately meaning deviation of 5% or less from the value provided.
[22]
22. Composition according to any one of claims 11 to 21, characterized in that the fat source comprises omega-3 fatty acids.
[23]
23. Composition according to claim 22, characterized by the fact that it comprises EPA and DHA.
[24]
24. Composition according to any one of claims 1 to 9, 11 to 12, 15 to 17 and 21 to 23, characterized by the fact that the carbohydrate content is in the range of 10-35 en% and in which the content of fat is in the range of 10-35 and n%.

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法律状态:
2017-10-24| B07D| Technical examination (opinion) related to article 229 of industrial property law|

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2017-12-12| B07D| Technical examination (opinion) related to article 229 of industrial property law|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

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2018-05-02| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa)|

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2018-06-12| B07D| Technical examination (opinion) related to article 229 of industrial property law|

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2018-08-21| B07B| Technical examination (opinion): publication cancelled|

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2018-08-28| B07B| Technical examination (opinion): publication cancelled|Free format text: ANULADA A PUBLICACAO CODIGO 7.4 NA RPI NO 2449 DE 12/12/2017 POR TER SIDO INDEVIDA. |

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2019-06-11| B07A| Technical examination (opinion): publication of technical examination (opinion)|

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2019-10-08| B09A| Decision: intention to grant|

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2019-11-26| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 23/12/2010, OBSERVADAS AS CONDICOES LEGAIS. (CO) 20 (VINTE) ANOS CONTADOS A PARTIR DE 23/12/2010, OBSERVADAS AS CONDICOES LEGAIS |

优先权:

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申请号 | 申请日 | 专利标题

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NLPCT/NL2009/050806|2009-12-24|

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NL2009000508|2009-12-24|

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PCT/NL2009/050806|WO2011078654A1|2009-12-24|2009-12-24|Low-caloric high-protein nutritional composition for the stimulation of muscle protein synthesis|

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PCT/NL2010/050887|WO2011078677A2|2009-12-24|2010-12-23|Low-caloric high-protein nutritional composition for the stimulation of muscle protein synthesis|

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