MXPA01008531A - Nutritional composition intended for specific gastro-intestinal maturation in premature mammals - Google Patents

Abstract

A nutritional enteral composition intended for favoring the growth and maturation of non-mature gastro-intestinal tracts of young mammals, which contains as a protein source a mixture of dietary protein hydrolysates and intact proteins being partly in the form of bioactive peptides.

Description

NUTRITIONAL COMPOSITION DESIGNED FOR SPECIFIC GASTROINTESTINAL MATURATION IN PREMATURE MAMMALS FIELD OF THE INVENTION This invention relates to an enteral composition containing peptides in an adapted profile size, bioactive peptides, intact proteins and free amino acids designed for specific gastrointestinal maturation in premature mammals.

BACKGROUND OF THE INVENTION Nutritional compositions based on protein hydrolysates such as milk or soy are commonly used in infant and clinical nutrition, and particularly in hypoallergenic formulas and formulas for patients suffering from various intestinal absorption problems. The use of free amino acids in nutritional compositions is also known, for example for patients suffering from diseases or particular conditions such as inflammatory bowel disease, intractable diarrhea, short bowel syndrome and the like. Accordingly, the amino acids are used alone or in combination with proteins or protein hydrolysates. Protein hydrolysates or mixtures of free amino acids are also used mainly in particular cases such as complete protein allergy. Another interest in using protein hydrolysates in nutrition is due to the fact that they are absorbed more rapidly in the intestine compared to complete proteins or free amino acids. However, it is not clear whether this faster absorption results in better nitrogen utilization, since studies that have been carried out so far have provided results that are inconclusive (Collin-Vidal et al; 1994; Endocrinol, Metab .. 30, E 907-914). In addition, this interest is in the sense of providing a source of amino acids that meets the patient's general amino acid needs and not in specifically meeting the needs of individual gastrointestinal maturation.

BRIEF DESCRIPTION OF THE INVENTION Accordingly, in one aspect, this invention provides a nutritional enteral composition designed to promote the growth and maturation of immature gastrointestinal tracts of young animals, which contains as a source of protein a mixture of protein hydrolysates of the diet and intact proteins that they are partially in the form of bioactive peptides.

In this composition, the protein hydrolysates of the diet preferably are in the form of a mixture of peptides of different size, free amino acids or a mixture thereof.

The protein hydrolysates in the diet can be hydrolyzed from animal proteins (such as milk proteins, meat proteins and egg proteins), or vegetable proteins (such as soy proteins, wheat proteins, rice proteins and peas proteins). ). The preferred source is milk protein.

The protein hydrolysates of the diet can be used as such or as isolated peptide fractions thereof. The hydrolyzed proteins can constitute at least 5% (by weight, of the total protein content calculated as nitrogen x 6.25) of the hydrolyzate having a degree of hydrolysis of about 40 and at least 5% of the hydrolysates have a lower degree of hydrolysis. The free amino acids and preferably in an amount of about 0 to 20% by weight of the total protein content (N x 6.25). The intact proteins may be individual or enriched protein fractions, of animal or vegetable origin, comprising whole milk, caseins, whey proteins, soy proteins or rice proteins, for example.

Preferably they are in an amount of at least about 5% of the total protein content (N x 6.25). The intact protein fraction can contain bioactive peptides such as TGF-β2 or a source of bioactive peptides such as β-casein released by the intestine by enzymatic hydrolysis. The final concentration of TGF-β2 can be in the range of 0.1 to 4 ng / mg of total protein, preferably about 1 to 2.5 ng / mg. The nutritional composition may also contain a source of fat and a source of carbohydrates. This composition preferably contains a source of protein and provides 5 to 30% of the total energy, a source of carbohydrates which provides 40 to 80% of the total energy, a source of lipids which provides 5 to 55% of the total energy , minerals and vitamins to meet daily needs. In another aspect, this invention provides the use of a selected mixture of intact protein and protein hydrolysates that is partially in the form of bioactive peptides for the preparation of a nutritional enteral composition to promote the growth and maturation of immature gastrointestinal tracts. or premature young animals. The nutritional composition also aims to meet the needs of very high nutrients for growth and development during that stage. It ensures optimal digestion and utilization (for tissue accretion) of the protein source and seeks to minimize the organism's nitrogen waste. In addition, a mixture of intact protein, protein hydrolysates, bioactive peptides and free amino acids provides a better source of amino acids to meet the patient's general amino acid needs as well as specifically favor the maturation of individual organs. The embodiments of the invention are described below only by way of example.

DETAILED DESCRIPTION OF THE INVENTION In the specification, the term "degree of hydrolysis" (DH) means the percentage of nitrogen in the form of free a-amino nitrogen, in comparison with total nitrogen. It is a measure of the degree to which proteins have been hydrolysed. The term "bioactive peptide" is related to: i) a protein or peptide present as such in the preparation and demonstrating specific functional properties, or ii) a protein or peptide that contains an amino acid sequence with specific properties, this sequence is released in the gastrointestinal tract during the natural digestion process. According to a first aspect of the invention, the nutritional composition comprises as a protein source a selected mixture of intact protein that is partially in the form of bioactive peptides and hydrolysates of dietary protein having a degree of hydrolysis in the range of about 5% to about 50% and free amino acids. The concentration of non-protein nitrogen of the protein source can constitute between 10% and 95% of total nitrogen. Such a protein source maximizes the area of the intestine in which the protein is digested and optimizes protein synthesis in the intestine and peripheral tissues. The nutritional composition can also contain a source of carbohydrates, a source of fats, vitamins and minerals. The intact protein can be any suitable diet protein; for example proteins of animal origin (such as milk proteins, meat proteins and egg proteins); proteins of vegetable origin (such as soy protein, wheat protein, rice protein and pea protein); or combinations thereof. Milk proteins such as casein and whey protein are particularly preferred. Preferably they are in an amount of at least about 5% of the total protein content (calculated as nitrogen x 6.25). It has been found that dietary protein in the form of intact protein increases the rate of muscle protein synthesis compared to protein hydrolysates. The hydrolysates of the diet protein can come from any suitable diet protein; for example proteins of animal origin (such as milk proteins, meat proteins and egg proteins); proteins of vegetable origin (such as soy protein, wheat protein, rice protein and peas protein); or combinations thereof. Milk proteins such as casein and whey protein are particularly preferred. The hydrolyzed diet proteins may comprise at least 5% (by weight, of the total protein content calculated as nitrogen x 6.25) of hydrolyzate having a degree of hydrolysis of about 40 and at least 5% of the hydrolysates having a lower degree of hydrolysis. In particular, hydrolysates having a degree of hydrolysis of about 10% to about 15% are found to increase the relative weight of the liver, as compared to mixtures of free amino acids. It has been found that hydrolysates having a degree of hydrolysis of about 15% to about 25% increase the protein concentration in the jejunum, the relative weight of the jejunum and the rate of protein synthesis in the jejunum. It has been found that the highly hydrolyzed protein, which has a degree of hydrolysis greater than 25% or which contains more than 25% by weight of dipeptides and tripeptides, more preferably more than 30%, increases the synthesis rate of protein in the jejunum and duodenum; particularly in the duodenum. The protein hydrolysates of the diet can be produced using methods which are well known in the art or can be obtained commercially. For example, nutritional formulas containing hydrolysates having a degree of hydrolysis of less than about 15% of Nestle Nutrition Company under the trademark Peptamen ™ are commercially available. Hydrolysates having a degree of hydrolysis greater than about 15% can be prepared using the procedure described in EP 0322589. The source of protein hydrolyzate in the diet can also be in the form of a mixture of free amino acids.; preferably so that the mixture provides a balanced profile of amino acids. The free amino acids are preferably in an amount of about 0 to 20% by weight of the total protein content (calculated as nitrogen x 6.25). It has been found that dietary protein in the form of a mixture of free amino acids increases the relative weight of the jejunum and the rate of protein synthesis in the jejunum. The total protein source preferably provides about 5% to about 30% of the energy of the nutritional composition; for example, approximately 10% to approximately 20% of the energy. The remaining energy of the nutritional composition can be provided in the form of carbohydrates and fats. If the nutritional composition includes a source of fat, the fat source preferably provides about 5% to about 55% of the energy of the nutritional composition; for example, approximately 20% to approximately 50% of the energy. The lipids that constitute the source of fat can be any suitable fat or fat blend. Vegetable fats are particularly suitable; for example soybean oil, palm oil, coconut oil, saffron oil, sunflower oil, corn oil, safflower oil, lecithins and the like. Fat of animal origin such as milk fats can also be added if desired. The lipids may also include medium chain triglyceride. For example, up to 60% by weight of lipids as medium chain triglyceride. Fractionated coconut oil is an adequate source of medium chain triglycerides. A source of carbohydrates can be added to the nutritional composition. Preferably it provides about 40% to about 80% of the energy of the nutritional composition. Any suitable carbohydrate can be used, for example sucrose, lactose, glucose, fructose, corn syrup solids and maltodextrins, and mixtures thereof. The fiber of the diet can also be added, if desired. In case it is used, it preferably comprises up to about 5% of the energy of the nutritional composition. The fiber of the diet can be in the form of any suitable origin, which includes for example soy, wheat, oats, pectin, guar gum and gum arabic.

Suitable vitamins and minerals can be included in the nutritional composition in an amount that satisfies the appropriate guidelines. One or more food grade emulsifiers may be incorporated into the nutritional composition, if desired; for example diacetyltartaric acid esters of monodiglycerides, lecithin and monoglycerides and diglycerides. Similar salts and stabilizers may be similarly included. The nutritional composition is preferably enterally administrable; for example, in the form of a powder, a liquid concentrate, a drink ready to be swallowed or ready to be administered. The nutritional composition can be prepared in any suitable way. For example, it can be prepared by combining the protein source of the diet, the carbohydrate source and the fat source, in appropriate proportions.

If they are used, emulsifiers can be included in the combination. Vitamins and minerals can be added at this point, but they are usually added later to avoid thermal degradation. Any lipophilic vitamin, emulsifier and the like can be dissolved in the fat source before the combination. The water, preferably water which has been subjected to reverse osmosis, can then be mixed in the form of a liquid mixture. The water temperature is conveniently from about 50 ° C to about 80 ° C to aid in the dispersion of the ingredients. Commercially available liquefied substances can be used to form the liquid mixture. The liquid mixture is then homogenized; for example in two stages. The liquid mixture can then be heat treated to reduce bacterial loads by rapidly heating the liquid mixture to a temperature in the range of about 80 ° C to about 150 ° C for about 5 seconds to about 5 minutes, for example. This can be carried out by steam injection, autoclaving or heat exchange; for example a plate heat exchanger. Subsequently, the liquid mixture can be cooled to about 60 ° C or about 85 ° C; for example by instantaneous cooling. The liquid mixture can then be homogenized again; for example in two stages from about 7 MPa to about 40 MPa in the first stage and from about 2 MPa to about 14 MPa in the second stage. The homogenized mixture can then be further cooled to add any heat-sensitive component; such as vitamins and minerals. The pH and solids content of the homogenized mixture is conveniently standardized at this point. If it is desired to produce a powdered nutritional composition, the homogenized mixture is transferred to a suitable drying apparatus such as a spray dryer and lyophilizer is converted to powder. The powder may have a moisture content of less than about 5% by weight. If it is desired to produce a liquid composition, the homogenized mixture is preferably filled aseptically in suitable containers by preheating the homogenized mixture (e.g. at about 75 to 85 ° C) and then injecting steam into the homogenized mixture to increase the temperature of the mixture. about 140 to 160 ° C; for example at approximately 150 ° C. The homogenized mixture can then be cooled, for example by instantaneous cooling to a temperature of about 75 to 85 ° C. The homogenized mixture is then homogenized, further cooled to about room temperature and filled into the containers. A suitable apparatus for carrying out specific filling of this nature is commercially available. The liquid composition can be in the form of a ready-to-ingest composition having a solids content of about 10 to about 14% by weight, or it can be in the form of a concentrate; usually the solids content is from about 20 to about 26% by weight. Flavors may be added to the liquid compositions so that the compositions are provided in a beverage form ready to be ingested with a little taste.

In another aspect, this invention provides a method for increasing the concentration and synthesis of proteins in the small intestine, the method comprising administering to a pture or immature mammal an effective amount of a nutritional composition containing hydrolyzate of the protein of the diet that they have. a degree of hydrolysis of less than 50% and intact proteins that are partially in the form of bioactive peptides.

In addition, the protein hydrolyzate of the diet preferably has a non-protein nitrogen concentration of at least about 85% total nitrogen. Non-protein nitrogen is defined as the fraction of nitrogen that is not recovered as a precipitate after acidification. Preferably, the method can be used to treat young pture or immature mammals to promote the growth and maturation of the gastrointestinal tract. Additionally, the method can also be applied to situations found in clinical nutrition, where alterations of normal growth or replacement of the intestinal mucosa occur, for example, after total parenteral nutrition or malnutrition for prolonged periods. The nutritional enteral composition also aims to cover very high nutrient needs for growth, development and maintenance during these situations. It ensures optimum digestion and utilization (for tissue accretion) of the protein source and attempts to minimize the waste of hydrogen from the body. The composition can also be used for patients with damage to the intestinal mucosa. The amount of the nutritional composition to be administered will vary based on the state of malnutrition or growth of the mammalian gut.

Example 1 Complete protein A quantity of 5 kg of whey protein is supplied (obtained from Meggle GmbH under the trade name Globulal 80) in demineralized water at 55 ° C to obtain a protein concentration (N * 6.38) of 10% by weight. The pH of the dispersion is adjusted by the addition of 190 g of calcium hydroxide and the dispersion is cooled to room temperature. The protein is then dried by lyophilization and packed in metal cans. The total proteins have a degree of hydrolysis of approximately 4.41% and a non-protein nitrogen concentration of approximately 1.1% based on total nitrogen.

Hydrolyzate 1 An amount of 6.25 kg of whey protein (obtained from Meggle GmbH) is dispersed in 50 liters of demineralized water at 55 ° C. The pH of the dispersion is adjusted to 8.2 by the addition of 1.8 liters of Ca (OH) 22M. The proteins are then hydrolyzed using 30 g of trypsin (salt-free pancreatic trypsin which has an activity of 6.8 AU / g and a quimotropsin content of less than 5% and which can be obtained from Novo Nordisk Ferment AG, Dittigen, Switzerland) . The hydrolysis reaction is continued for 4 hours at 55 ° C. During the reaction, pH 7.4 is regulated by the addition of 1.6 N NaOH and 0.4 N KOH. The enzymes are then quenched by heating the reaction mixture to 80 ° C and maintaining the mixture at this temperature for about 5 minutes. The mixture is then cooled to 16 ° C. The hydrolysed proteins are then dried by lyophilization and packed in metal cans. The hydrolyzate has a hydrolysis degree of about 14% and a nonprotein nitrogen concentration of about 54% based on the total nitrogen.

Hydrolyzate 2 An amount of 6.25 kg of whey protein (obtained from Meggle GmbH) is supplied in 50 liters of demineralized water at 55 ° C. The pH of the dispersion is adjusted to 7.5 by the addition of 1.6 liters of Ca (OH) 2 IM and 162 ml of a 1.6M NaOH solution and 0.4M KOH. The proteins are then hydrolysed using 50 gm of trypsin (available from Novo Nordisk Ferment AG). The hydrolysis reaction is continued for 4 hours at 55 ° C. During the reaction, the pH is regulated to 7.4 by the addition of 1.6N NaOH and 0.4N KOH. The enzymes are then inactivated and the unhydrolyzed protein is denatured, by heating the reaction mixture to 90 ° C and maintaining the mixture at this temperature for about 5 minutes. The mixture is then cooled to 56 ° C and hydrolyzed again for 1 hour using 50 g of trypsin at 55 ° C. During the reaction, the pH is regulated to 7.4 by the addition of 1.6 N NaOH and 0.4 N KOH. The enzymes are then quenched by heating the reaction mixture to 80 ° C and maintaining the mixture at this temperature for about 5 minutes. The mixture is then cooled to 18 ° C. The hydrolysed proteins are then dried by lyophilization and packed in metal cans. The hydrolyzate has a degree of hydrolysis of about 17.3% and a non-protein nitrogen concentration of about 65.9% based on the total nitrogen.

Hydrolyzate 3 An amount of 6.25 kg of whey protein (obtained from Meggle GmbH under the t name Globulal 80) is dispersed in 50 liters of demineralized water at 55 ° C. The pH of the dispersion is adjusted to 7.5 by the addition of 1.6 liters of Ca (OH) 2 IM and 162 ml of a 1.6M NaOH solution and 0.4M KOH. The proteins are subsequently hydrolyzed using 250 g of Alcalase 2.4L (EC 940459 - obtainable from Novo Nordisk Ferment AG). The hydrolysis reaction continues for 4 hours at 55 ° C. For the first hour of the reaction, the pH is regulated to 7.6 by the addition of 1.6 N NaOH and 0.4 N KOH. An amount of 250 g of Neutrase and 0.5 L (which can be obtained from Novo Nordsk Ferment AG) is added and the proteins are further hydrolyzed for 4 hours at 50 ° C. The enzyme is subsequently inactivated by heating the reaction mixture to 90 ° C and maintaining the mixture at this temperature for approximately 5 minutes. The reaction mixture is subsequently cooled to 55 ° C. The pH of the reaction mixture is adjusted to 7.33 by the addition of 1.6N NaOH and 0.4N KOH, and the reaction mixture is hydrolyzed again for 4 hours using 100 g of pancreatin at 55 ° C. During the reaction, the pH is regulated to 7.5 by the addition of NaOH ÍM. The enzymes are then inactivated by heating the reaction mixture to 90 ° C and maintaining the mixture at this temperature for about 5 minutes. The mixture is subsequently cooled to 4 ° C. The hydrolysed proteins are subsequently dried by lyophilization and packed in metal cans. The hydrolyzate has a degree of hydrolysis of about 35% and a concentration of non-protein nitrogen of about 92.6% based on the total nitrogen.

Example 2 In order to obtain a nutritional composition designed for specific gastrointestinal maturation in premature mammals, the following mixture is prepared: i) 14.5 g / 100 g of total pulverized protein content: 10% of the hydrolyzate 2, as prepared in example 1 , 40% of the hydrolyzate 3, as prepared in example 1, 50% of intact proteins (containing 1 ppm of TGFß2), ii) 26 g / 100 g of fat powder: 40% medium chain triglycerides 60% long chain triglycerides iii) 53.6 g / 100 pulverized carbohydrates 65% lactose 35% maltodextrin iv) and vitamins and minerals to meet daily needs.

Claims (7)

1. Nutritional enteral composition designed to promote the growth and maturation of immature gastrointestinal tracts of young mammals, which contains: a mixture of hydrolyzed protein of the diet having a degree of hydrolysis in a range from about 10% to less than 50% by weight and which are in the form of a mixture of peptides of different size and free amino acids, the free amino acids are present in an amount of up to about 20% (each, calculated as nitrogen x 6.25), - the intact proteins are partially in the form of bioactive peptides.

2. The composition, as described in claim 1, wherein the protein hydrolysates of the diet contain about 5% (by weight, of the total protein content calculated as nitrogen x 6.25) of hydrolyzate containing a degree of hydrolysis of about 40%. % and at least about 5% of hydrolysates that have a lower degree of hydrolysis.

3. The composition, as described in any of the preceding claims, wherein the intact proteins are present in an amount of at least about 5% by weight of the total protein content.

4. The composition, as described in any of the preceding claims, wherein the intact proteins are milk proteins, whey proteins, caseins and bioactive proteins, such as TGF-β.

5. The composition, as described in any of the preceding claims, wherein the bioactive peptides represent at least about 0.1 to about 4 ng / mg of total protein.

6. The composition, as described in any of the preceding claims, which consists of a protein source that provides 5 to 30% of the total energy, a source of carbohydrates, which provides 40 to 80% of the total energy, a lipid source, which provides 5 to 55% of the total energy, minerals and vitamins to meet daily requirements.

7. Use of a composition, as described in any of the preceding claims, for the preparation of a nutritional enteral composition designed to promote the growth and maturation of immature gastrointestinal tracts of young mammals.