JP2681121B2 - Nutritional composition containing oligopeptide of L-glutamine - Google Patents

Description

The present invention relates to a nutritional composition, more specifically, an L-glutamine (Gln) oligopeptide, which contains an amino acid formulation suitable for nutritional supplementation during various diseases. , For example, a composition used as an infusion solution.

[Conventional technology]

Intravenous amino acid infusions provide nutritional support when oral or insufficient intake of amino acids or proteins is necessary despite various diseases or preoperative and postoperative needs. Widely used for purposes.

It is known that, when an amino acid is administered intravenously, it is extremely important to replenish the essential or non-essential amino acids without bias in view of the bioavailability. Almost all amino acid transfusions that have already been put into practical use are based on this idea except for special pathological conditions. Further, it is known that a certain amino acid group plays an extremely important role at the time of disease.

By the way, regarding Gln, which is a kind of non-essential amino acid, a specific infusion solution has not been developed yet.
This is because Gln was very unstable and liable to be decomposed, and there was a problem in pharmaceutics, and its role in the living body was not clarified, so that the necessity was not recognized. Therefore, the fact is that the prescription has not been examined.

However, the recent rapid progress in research on amino acid metabolism during diseases has revealed the importance of Gln. The main roles of this Gln have been to improve nitrogen balance during various invasions and stresses, and prevent gastrointestinal mucosal atrophy, which is a serious complication of total parenteral nutrition (TPN). Amino acid infusions containing Gln have been demanded because they have effects, wound healing effects and anti-ulcer effects.

Several experimental formulations have already been disclosed for amino acid infusions containing Gln [(a) DE320678;
(B) Essential amino acid research No. 116, 24 (1987); (c) Sur
gical Forum 37 , 56 (1986)].

However, in the above (a), only the use of acylated Gln as a new stabilized infusion material is disclosed, and the formulation and its effect are not examined in detail. In the examples disclosed in (b) and (c), the biological effect was examined by adding a certain amount of unstable crystalline Gln to a commercially available amino acid infusion solution, and a formulation that can be put to practical use is shown. Not not.

[Problems to be solved by the invention]

An object of the present invention is to provide an amino acid-containing nutritional composition having a new formulation, which contains unstable Gln without any pharmaceutical limitation and exhibits an excellent nutritional effect in various diseases.

[Means for solving the problem]

Gln is most abundant in plasma and intramuscular amino acid pools, and especially in skeletal muscle, Gln accounts for 61% or more than half of the amino acid pool.

The branched-chain amino acids (BCAA) of L-leucine, L-isoleucine, and L-valine are also contained in skeletal muscle in large amounts, like Gln.

Furthermore, Gln and BCAA both play important roles in improving energy production and nitrogen balance, and are thought to be closely related to metabolic pathways.

Therefore, the present inventors have found that when formulating amino acid formulations that exert excellent effects in various diseases, the amount of Gln and BCAA
It was thought that there is a peculiar relationship with the compounding amount of, and the study was carried out diligently together with pharmaceutical stabilization. As a result, the instability of Gln can be solved by using it as an oligopeptide, and in order to make the effect of Gln more effective,
It was found that there is a correlation not only with the mixing ratio of ln and BCAA but also with the mixing ratio of other amino acids, and the present invention has been completed.

That is, the present invention provides essential amino acids and non-essential amino acids with glycyl-L-glutamine, L-alanyl-L-glutamine, L-leucyl-L-glutamine, L-isoleucyl-L-glutamine, L-valyl-L-glutamine,
A composition comprising at least one glutamine oligopeptide selected from the group consisting of L-leucyl-L-glutaminyl-glycine and L-leucyl-L-glutaminyl-L-alanine, wherein the glutamine oligopeptide is an amino acid. When converted to, contains at least the following amino acids within the following range, The weight ratio of the total amount of branched chain amino acids (BCAA) to the total amount of L-glutamine is 0.11 to 7.50, and
The weight ratio of BCAA total amount is 0.18 to 0.46, and the weight ratio of the total amount of non-essential amino acids to be the total essential amino acids is 0.50 to 1.80, which provides a nutritional composition capable of preventing gastrointestinal mucosal atrophy. The above-mentioned "when the glutamine oligopeptide is converted into amino acids" means "when the compounded amount of the glutamine oligopeptide is converted into the amount of each amino acid produced when completely hydrolyzed".

Examples of the Gln oligopeptide used in the present invention include glycyl-L-glutamine (Gly-Gln), L-aralyl-L-glutamine (Ala-Gln), and L-leucyl-L.
-Dipeptides such as glutamine (Leu-Gln), L-isoleucyl-L-glutamine (Ile-Gln), L-valyl-L-glutamine (Val-Gln) or L-leucyl-L
-Glutaminyl-glycine (Leu-Gln-Gly), L-leucyl-L-glutaminyl-L-alanine (Leu-Gln-
Tripeptides such as Ala) can be mentioned. These peptides can be produced according to a conventional peptide synthesis method.

The amino acids and oligopeptides according to the present invention are not only in the free form but also in pharmacologically acceptable salts, for example, metal salts with sodium, potassium, etc., mineral salts with hydrochloric acid, sulfuric acid, etc. or acetic acid, lactic acid etc. It can be used in the form of organic acid salts. Amino acids other than Gln may be used as pharmacologically acceptable N-acyl derivatives, ester derivatives or oligopeptides.

Although the nutritional composition of the present invention is often used as an infusion solution, it may be used as a solid preparation such as tablets, granules or fine granules for patients who can be orally administered.
Any of the preparations can be manufactured according to a known method using a stabilizer, a pH adjuster, an excipient and the like which are usually used.

(Operation)

Since Gln was used as an oligopeptide, a pharmaceutically stable amino acid formulation containing a Gln component could be constructed. The formulation of the present invention, that is, the nutritional composition exerts an excellent nutritional effect against various diseases including prevention of gastrointestinal mucosal atrophy, which is a complication when TPN is performed. The oligopeptide according to the present invention is effectively used in the living body.

[Example 1] Ala-Gln 24.2g was added to the amino acid composition shown in Table 1 and dissolved by heating in distilled water for injection to a total amount of 0.99, and then the pH was adjusted to 6.5 with an acetic acid aqueous solution, and then the total amount. Was set to 1.
This aqueous solution was filtered through a membrane filter having a pore size of 0.45μ, filled in a 200 ml glass bottle, replaced with nitrogen gas, and then sealed. High-pressure steam was sterilized to prepare an infusion solution for intravenous administration.

When the dipeptide is converted into each amino acid, Al
It becomes a9.9g and Gln 16.3g.

[Example 2] Ala-Gln19.3g, Ile- in the amino acid composition shown in Table 2 was used.
Gln15.0g and Val-Gln5.9g were added, and an intravenous infusion solution was prepared in the same manner as in Example 1 below.

When the above-mentioned three kinds of dipeptides are converted into respective amino acid components, Ala7.9g, Ile7.6g, Val2.8g and Gln25.0g are obtained.

[Example 3] Gly-Gln22.6g was added to the amino acid composition shown in Table 3, and an intravenous infusion solution was prepared in the same manner as in Example 1 below.

When the dipeptide is converted into each amino acid component, Gly8.3 g and Gln 16.3 g are obtained.

[Examples 4 to 16] The amino acids and oligopeptides shown in Tables 4 to 6 were mixed, and an intravenous infusion solution was prepared in the same manner as in Example 1 below.

[Test Example 1] SD male rats weighing 170 to 180 g were placed in a right external jugular vein with a silicone rubber catheter, and infused for 1 week by total parenteral nutrition.

The administered infusion solution had the same composition of sugars, electrolytes, vitamins and trace elements but different amino acid composition. As amino acids, the infusion solutions of Examples 1, 2, 3, 4, and 12 and the comparison solution having the formulation shown in Table 7 below were used.

The effect was examined by the small intestine function, and the indexes were jejunal weight, jejunal mucosal thickness, jejunal villous height, and jejunal mucosal DNA. The results are shown in Table 8, and a clear improvement can be confirmed as compared with the comparative solution.

[Test Example 2] Male SD rats (5 / body weight) weighing 160 to 170 g, which were fasted overnight
5-fluorouracil (5-FU) 200 mg was orally administered to the group) to prepare a small intestinal disorder model. Then, under anesthesia, a silicone rubber catheter was placed in the right external jugular vein, and the infusion solution was administered for 5 days by total parenteral nutrition. As the infusion solution, the amino acid infusion solutions of Examples 2 and 3 and the comparative solution A shown in Table 7 were used. The nutritional effect (change in body weight,
Cumulative nitrogen balance) and air-membrane mucosal enzyme activities (alkaline phosphatase activity, sucrase activity) were examined as indicators of small intestinal function.

The results are shown in FIGS. 1 and 2 and Table 9, and the amino acid infusion solutions of Examples 2 and 3 were found to have a significantly superior nutritional effect and high jejunal mucosal enzyme activity as compared with Comparative Solution A.

[Effects of the Invention] According to the present invention, it is intended to provide an amino acid-containing nutritional composition of a novel formulation containing unstable Gln without being subjected to pharmaceutical restrictions and exhibiting an excellent nutritional effect during various diseases. You can

[Brief description of the drawings]

FIG. 1 shows changes in body weight gain of rats with small bowel disorder administered by infusion, and FIG. 2 shows cumulative nitrogen balance.

Claims (1)

(57) [Claims] 1. An essential amino acid and a non-essential amino acid are glycyl-L-glutamine, L-alanyl-L-glutamine,
L-leucyl-L-glutamine, L-isoleucyl-L
-Glutamine, L-valyl-L-glutamine, L-leucyl-L-glutaminyl-glycine and L-leucyl-
A composition containing at least one glutamine oligopeptide selected from the group consisting of L-glutaminyl-L-alanine, wherein when the glutamine oligopeptide is converted into amino acids, at least the following amino acids are within the following range: Contains, The weight ratio of the total amount of branched chain amino acids (L-leucine, L-isoleucine and L-valine) to the total amount of L-glutamine was 0.11 to 7.50, and the weight ratio of the total amount of branched chain amino acids to the total amount of amino acid was 0.18 to 0.46. A nutritional composition capable of preventing gastrointestinal mucosal atrophy, wherein the weight ratio of the total amount of non-essential amino acids to the total amount of essential amino acids is 0.50 to 1.80.