JPS6326733B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to nutritional compositions for mammals. More particularly, the present invention relates to oligopeptide-containing nutritional compositions and methods of administering the same to mammals. The invention described herein was made in the course of research conducted under a grant or award from the Department of Health, Education, and Welfare of the United States. Humans and other mammals require protein every day for sufficient life activities. Proteins are converted into amino acids in the digestive system, and the amino acids produced are used by the body for growth, growth, reproduction, and anabolism. The human body has essential amino acids such as lysine, leucine, isoleucine, tryptophan,
Requires daily supply of methionine, valine, phenylalanine and threonine. Other amino acids are called "non-essential" and are used by the body as a source of oxygen. Non-essential amino acids are alanine, glycine,
These are serine, proline, histidine, tyrosine and cysteine. When essential amino acids are lacking, nutritional status rapidly deteriorates and virtually every organ in the body malfunctions, ultimately resulting in various health problems such as liver damage, anemia, infection, etc.
This results in diarrhea and growth retardation. In the case of protein deficiency or medical inability of the patient to assimilate proteins, intravascular or gastrointestinal administration of free amino acids as a solution is possible. 1970
The basic diet widely used in medical practice in the 2000s used such free amino acid solutions. However, these solutions are highly osmotic (hypertonic). Hypertonic solutions are poorly tolerated both in the intestine and in the blood vessels and can lead to undesirable effects such as diarrhea and dehydration. These issues are critical for affected patients. Although the body assimilates amino acids, the body's transport systems can make better use of peptides, absorbing them and then hydrolyzing them into amino acids within the body's cells. According to very recent discoveries, the human digestive system comprises separate sites for dipeptide and tripeptide absorption in the intestinal mucosa. Upon absorption, dipeptides and tripeptides are hydrolyzed into their component amino acids. Therefore, hydrolysis occurs after the peptide is taken up into body cells. [Adibi and
Soleimanpour, J.Clin.lnvest.53:1368–1374
(1974). ] The peptide transport system has the following aspects: (a) The system takes in dipeptides and tripeptides without taking in amino acids. (b) This system has little or no affinity for peptides with three or more amino acid residues. (c) This system has a higher maximum uptake rate than amino acid-loaded systems. (d) This system favorably incorporates peptides with lipophilic amino acids in the N-terminal position. (e) The system is most active in the jejunum, least active in the duodenum, and intermediate in the ileum. Basic diets using free amino acids are usually hypertonic. Hypertonicity poses a second set of problems for medical patients with gastrointestinal disorders. There are various reports regarding the clinical research evaluation of single use of dipeptide or single use of tripeptide. However, there still remains a problem in administering sufficient amino acid nutrients to mammals, such as human medical patients, in a form that allows the amount of amino acids to be assimilated by the transport system without the adverse effects of hypertonicity. According to the invention there is provided a nutritional composition which is an aqueous solution of oligopeptides [dipeptides and/or tripeptides], in which each oligopeptide has a glycine residue as its N-terminal amino acid group. The aqueous solution of the oligopeptide can be provided at the same osmolality as the corresponding free amino acid solution and at twice (in the case of dipeptides) or three times (in the case of tripeptides) the amino acid concentration.
Furthermore, oligopeptides are easily assimilated by transport systems and easily converted into amino acid residues. In somatic cells, the oligopeptide according to the invention has a glycine group as the N-terminal group of the oligopeptide. The glycine-terminated oligopeptide is transported into cells in the intact form of the desired oligopeptide. The glycine group preserves the oligopeptide from hydrolysis to amino acids by the action of peptidases on the cell membrane. Premature hydrolysis of oligopeptides to amino acids will disturb the osmolality of the system. The glycine group is also lipophilic and the oligopeptide has increased transport across cell membranes. Oligopeptides are cleaved into their component amino acids inside somatic cells. Since glycine-terminated oligopeptides are particularly water-soluble, utilization of these oligopeptides in high concentrations is achieved. This aspect is particularly important in the treatment of patients who are placed on water-restricted diets, such as certain heart disease patients and kidney disease patients. The glycine-terminated oligopeptide has good thermal stability, allowing it to be autoclaved. Glycine-terminated oligopeptides in solution also have good shelf-life stability. oligopeptides with other nutritional compositions such as fats,
May be injected intravenously with glucose, sugars, minerals, trace elements and vitamins. The oligopeptide solution may also be introduced elsewhere in the gastrointestinal tract orally or by other gastrointestinal administration techniques such as gastric tubes and insertion tubes. The oligopeptide solution contains about 1-20% by weight oligopeptide, preferably about 1-5% by weight.
This aqueous solution is an electrolyte solution suitable for intravenous injection or for gastrointestinal administration. The aqueous solution itself may contain other nutritional additives such as fats, polyols, glucose, mono- or oligosaccharides, minerals, trace elements and vitamins. According to the present invention, aqueous dietary compositions containing at least two tripeptides or at least two dipeptides or "a mixture comprising at least one dipeptide and at least one tripeptide" are produced. . The term oligopeptide herein encompasses dipeptides and tripeptides. The oligopeptide includes a glycine residue and one or two other essential amino acid residues such as lysine, leucine, isoleucine, tryptophan, methionine, valine, phenylalanine, threonine;
Alternatively, non-essential amino acids such as arginine, histidine, alanine, proline and glutamic acid are included. The glycine residue is the N-terminal residue of the oligopeptide. The oligopeptide concentration in the aqueous solution is 1-20% by weight, preferably 1-5% by weight. Approximately 2.5% by weight
Aqueous solutions containing oligopeptides have useful biological absorption properties. The selection of oligopeptides in this composition depends on the requirements for essential and non-essential amino acids. A representative tripeptide mixture is shown in Table 1. The mixture shown in Table 1 is intended to approximate approximately one dose (850 mg) of protein of high biological value. The mixture in Table 1 is 1
contains useful nutritional compositions dissolved in water. Table 1: Total amount 850 mg/(water) Tripeptide amount (mg) Glycine-leucine-leucine 77 Glycine-isoleucine-isoleucine 59 Glycine-valine-valine 70 Glycine-threonine-threonine 53 Glycine-methionine-methionine 71 Glycine-phenyl Alanine-phenylalanine
75 Glycine-Lysine-Lysine 57 Glycine-Tryptophan-Tryptophan 21 Glycine-Alanine-Alanine 367 The first eight tripeptides in Table 1 provide all of the essential amino acids. The last glycine-alanine-alanine tripeptide satisfies the non-essential amino acid requirement. The chemical structure of glycine-leucine-leucine is as follows: glycine unit

The formula provides the N-terminal group in the tripeptide or dipeptide. Dipeptide compositions for preparing dipeptide 1 aqueous solutions are shown in Table 2. This composition provides a person's daily amino acid requirements. It will be appreciated that this dipeptide contains a glycine residue as the N-terminal residue. Table 2: Total amount of 1 g of aqueous dipeptides Glycine -Isoleucine 2.5 Glycine-Leucine 3.5 Glycine-Lysine 3.1 Glycine-Methionine 3.2 Glycine-Phenylalane 3.3 Glycine-Threonine 1.6 Glycine-Tryptophan 0.63 Glycine-valine 2.5 Glycine-Arginine 5.9 Glycine-Histidine 1.5 Glycine-Alanine 5.4 Glycine-Glutamic Acid 6.9 Glycine-Proline 5.8 Method of Administration The aqueous oligopeptide solution according to the invention is administered orally together with other nutrients such as vitamins, fats, polyols, glucose, oligosaccharides, minerals and conventional foods made from trace elements. can be ingested. In the case of parenteral administration, the oligopeptide solution to be supplied can be administered via a Y-tube in combination with a glucose solution or other parenteral solution to be supplied at the same time. In preferred embodiments, the oligopeptide solution may be mixed with a polyol solution, glucose solution, and/or other parenteral solutions to form a mixture that can be administered parenterally. Solutions containing oligopeptides and polyols are particularly useful. Suitable polyols are carbohydrate alcohols such as sorbitol and xylitol.
Solutions of oligopeptides and polyols can be heated without causing undesirable reactions between the oligopeptides and polyols. This is different from the reaction that occurs when a glucose solution is heated with an oligopeptide solution. The same oligopeptide mixture for oral use can also be used for parenteral nutrition. In medical practice, we often encounter situations in which it is not possible to orally administer the daily nutritional requirements of a patient. Dudrick et al, Surgery 64:134-142, 1968
The research and development of parenteral complete nutrition has enabled intravenous injection with sufficient energy and essential nutrient requirements. Intravenous solutions currently in use are made from free amino acids and are therefore hypertonic. The solution must therefore be administered via a catheter placed in the great central vein, which is often considered a surgical procedure. This central venous method for parenteral nutrition has been reported to be associated with complications such as infection.
In addition, complications such as venous thrombosis, dehydration and drowsiness may occur as a result of hypertonic solution injection. Oligopeptide administration instead of free amino acid administration allows the administration of a solution of the same amount of amino acid residues that is not hypertonic and thus allows introduction of the solution into peripheral veins. Moreover, this procedure cannot be considered a surgical procedure. The oligopeptide concentration in the intravenous solution should be similar to the amino acid composition in current free amino acid solutions, which have been shown to be sufficient for protein nutrient retention. The oligopeptides of the composition according to the invention are water-soluble. Preferably the composition also contains certain oligopeptides of non-essential amino acids for nitrogen supply. This composition allows the oligopeptide to be transported into cells as it is, and then undergoes intracellular hydrolysis. Intravenous injection of the oligopeptide results in increased insulin production compared to that resulting from intravenous injection of the corresponding free amino acid. After intravenous injection, the oligopeptide disappears rapidly, indicating that the oligopeptide is rapidly utilized. Utilization rate is rapid in kidney tissue; slower in muscle tissue. Although the invention has been described in connection with certain specific embodiments, various changes may be made in shape and arrangement of steps to accommodate various needs without departing from the spirit and scope of the invention. This will be readily apparent to those skilled in the art. This invention was carried out in the course of research conducted under a grant or award from the Department of Health, Education, and Welfare, United States.

Claims (1)

[Claims] 1. Contains an aqueous solution containing at least two oligopeptides selected from the group consisting of dipeptides and tripeptides, provided that the oligopeptides contain one or more oligopeptides.
1. A nutritional composition comprising 3 glycine units, the glycine unit being the N-terminal amino acid residue of an oligopeptide. 2. The nutritional composition according to claim 1, wherein the oligopeptide is contained in an amount of 1 to 20% by weight of the aqueous solution. 3. The nutritional composition according to claim 1, wherein the aqueous solution is an electrolyte solution. 4 The tripeptide is glycine-leucine-leucine, glycine-isoleucine-isoleucine, glycine-valine-valine, glycine-threonine-threonine, glycine-methionine-methionine, glycine-phenylalanine-phenylalanine, glycine-lysine-lysine, and Glycine
The nutritional composition according to claim 1, characterized in that it is selected from the group consisting of tryptophan-tryptophan. 5. The nutritional composition according to claim 1, characterized in that it contains other nutrients selected from the group consisting of fats, polyols, glucose, oligosaccharides, minerals, trace elements, and vitamins. 6. The nutritional composition according to claim 1, comprising an oligopeptide having amino acid residues of all essential amino acids. 7. A nutritional composition comprising the composition according to claim 6, which contains at least one oligopeptide of non-essential amino acids. 8 The dipeptide is glycine-isoleucine, glycine-leucine, glycine-lysine, glycine-
A nutritional composition according to claim 1, characterized in that it is selected from the group consisting of methionine, glycine-phenylalanine, glycine-threonine, glycine-tryptophan and glycine-valine. 9. The nutritional composition of claim 5, wherein the other nutrients include one or more carbohydrate alcohols. 10. The nutritional composition according to claim 9, wherein the carbohydrate alcohol is sorbitol or xylitol.