JPH02286624A - N-acylated dipeptide-containing amino acid transfusion solution containing reducing sugar blended therein - Google Patents

Abstract

PURPOSE:To obtain a nutritionally excellent complex transfusion solution capable of simultaneously blending a reducing sugar with amino acid and electrolyte and inhibiting a browning phenomenon by using tryptophan in the form of an N-acylated dipeptide. CONSTITUTION:An amino acid transfusion solution containing a reducing sugar blended therein and an N-acylated dipeptide in which the C-terminal of a dipeptide is L-tryptophan and the N-terminal thereof is acylated (acetyl, propionyl, lactyl or maleyl is preferred as the acyl group). Glycine, L-alanine, L-leucine, L-isoleucine, L-valine, L-threonite, L-serine, L-glutamic acid or L- aspartic acid is used as the amino acid at the N-terminal of the above-mentioned dipeptide.

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention relates to an amino acid infusion containing reducing sugar, and more specifically, a nutritional solution that can simultaneously contain sugar, amino acids, and electrolytes by using an N-acylated dipeptide. This invention relates to a comprehensive infusion solution with an excellent composition.

[Conventional technology]

Intravenous amino acid infusion is a nutritional supplement when amino acids or proteins need to be ingested during various diseases or before and after surgery, but cannot be taken orally or the intake is insufficient. It is widely used for this purpose.

However, if there is insufficient heat in the body, some of the amino acids administered will not be utilized. Therefore, it is desirable to incorporate reducing sugars such as glucose, fructose, or maltose in advance for effective utilization of amino acids, but these reducing sugars may undergo the Maillard reaction with amino acids during autoclaving or during storage. It was not preferable to mix the two, as this would cause the infusion to turn brown, and the presence of an electrolyte would further accelerate the browning. Therefore, the reducing sugar and amino acid are administered together or separately when used, but there is an increased chance of contamination with various microorganisms during mixing.

By the way, regarding amino acid infusion containing reducing sugar,
Several methods have already been disclosed. A method has been proposed to use L-1-lyptophan, which is considered to be a major cause of browning, by N-acylating it (Japanese Unexamined Patent Application Publication No. 1983-1999).
115909.56-26467). However, L
- Even if tryptophan is used in the N-acylated form, it cannot be said that its utilization rate in the body is necessarily good. Also,
JP-A-61-78719.62-22162L58-1
No. 67516 discloses an infusion solution characterized by using lactic acid as an organic acid salt and adjusting the pH to 4.5 to 5.5. However, it cannot be said to be sufficient in terms of stability.

[Problem to be solved by the invention]

The object of the present invention is to simultaneously combine reducing sugars, amino acids, and electrolytes in a well-balanced manner to achieve a nutritionally excellent effect, and to suppress browning by using milu-L-tryptophan (Acetyl-Glu-Trp), N-acetyl -Asparatyl-L-tryptophan (occety
l-Asp-Trp), N-propionyl L-alanyl-L-tryptophan, N-lactyl-L-alanyl-L-tryptophan, N-oleyl-L-alanyl-
L-tryptophan and N-maleyl-L-alanyl-
The object of the present invention is to provide a stable reducing sugar-containing amino acid infusion by incorporating an N-acylated dipeptide selected from L-tryptophan. The N-acylated dipeptide used in the present invention is characterized by having an L tryptophan (Trp) residue at the C-terminus of the dipeptide. Trp is rapidly generated in the liver and kidneys and has a high bioavailability.

In the composition of the present invention, the reducing sugar is not particularly limited as long as it can be used as a heat source in the living body, but glucose, maltose, and fructose are preferred, and a mixture of these can also be used. The purpose of the present invention is to inhibit amino acids and N-acyl.

[Means to solve the problem]

In view of the current situation as described above, the present inventors have carried out various studies and have found that by converting tryptophan, which is considered to be a major cause of browning, into an N-acylated dipeptide, it is possible to prevent coloring of infusion fluids, and to further improve the They discovered that it can be effectively utilized within the body and completed the present invention.

That is, the present invention converts L-tryptophan (Trp) into N
-acetyl-glycyl-tryptophan (Acet)
yl-Gly-Trp), N-acetyl-L-alanyl-L-tryptophan (Acetyl-Ala-Tr
p), N-acetyl-L-leucyl-L-tryptophan (Acetyl-Leu-Trp), N-acetyl-L-isoleucyl-L-tryptophan (Δcety
l-11e-Trp), N-acetyl-L-valyl-L
-Tryptophan (Acetyl-Val-Trp)
, N-Acetyl-Threonyl-Thr-Trp, N-Acetyl-Seryl-L-Tryptophan (Acetyl-Ser)
-Trp), N-acetyl-glutated dipeptide can be used not only in free form but also in pharmacologically acceptable salts, such as metal salts such as sodium and potassium, mineral salts such as hydrochloric acid and sulfuric acid, or acetic acid and lactic acid. can be used in the form of organic acid salts.

The pH of the present invention is preferably 4.5 to 6.5, and may contain substances such as stabilizers and T)H regulators.

Furthermore, the composition of the present invention can be manufactured according to a commonly used manufacturing method for infusion solutions and subjected to high-pressure steam sterilization.

[Effect]

The N-acylated dipeptide according to the present invention is stable in a 7.5x glucose solution, and as shown in Table 1, the N-acylated dipeptide is stable in a 7.5x glucose solution.
Under high pressure steam sterilization at 5°C for 60 minutes, the browning phenomenon is clearly superior to that of Trp.

The composition thus obtained is nutritionally excellent and can suppress the browning phenomenon, and can be effectively utilized in living organisms.

The present invention will be explained in more detail by showing test examples and examples below.

Table 1 Stability of amino acids and N-acylated dipeptides (Note)
Autoclave sterilization involves heating a 7.5x glucose solution containing 0.1x amino acids or N-acylated dipeptides to 105°C.
The test was carried out for 160 minutes.

Glucose 7.5g Potassium acetate 1.47g Potassium phosphate
0.68g Magnesium sulfate heptahydrate
1.2g Sodium chloride 1.34g
Calcium gluconate monohydrate 1.3 g [Example 2] Acetyl-Gly-Trpo was added to the composition shown in Table 3.
, 5g was added thereto, and a comprehensive infusion solution was prepared in the same manner as in Example 1.

This formulation contains cty N-acetyl dipeptide.

When converted to Trp, they are 0.12g/Il and 0.12g/Il, respectively.
It becomes 32g/Il.

[Example 1] Acetyl-Ala-Trpo was added to the composition shown in Table 2.
, 6g was added, dissolved in distilled water for injection, and adjusted to pH with acetic acid solution.
was adjusted to 4.5 to 5.5, and then the total amount was set to 11.

This solution was filtered through a Millipore filter with a pore size of 0.45 μm, filled into a 500 ml infusion vial, and sterile nitrogen gas was blown into the vial for 30 seconds. This was sterilized using high-pressure steam to prepare a comprehensive infusion preparation.

This preparation has acetyl dipeptides of 0.17 g/l and 0.39 g/l when converted to Ala and Trp, respectively.
It becomes g/E.

Table 2 Table 3 Glucose potassium acetate phosphate-potassium magnesium sulfate heptahydrate Sodium chloride calcium gluconate monohydrate 7.5g 1.47g 0.68g 1.2g 1.34g 1.3g [Example 3] Table 4 shows Acetyl-Val-TrpO in the composition shown.
, 8 g was added thereto, and a comprehensive infusion solution was prepared in the same manner as in Example 1.

This formulation contains N-acetyl dipeptide at Val.

When converted to Trp, each is 0.27g#! , 0.4
It becomes 7g/42.

Table 4 Table 4 continued Glucose 7.5g Potassium acetate 1.47g Potassium phosphate
0.68g Magnesium sulfate heptahydrate
1.2g Thorium chloride 1.34g Calcium gluconate monohydrate 1.3g [Examples 4 to 8] Reducing sugar, amino acid, electrolyte (same composition as Example 1) shown in Table 5, and N-acylated dibepdide Comprehensive infusion preparations 4 to 8 were prepared in the same manner as in Example 1.

Table 5 (Table 5 note) 1. The amount of amino acids in the table is g/! It is shown by .

2. Other amino acids refer to the amount of other amino acids other than tryptophan in N-acetyl dipeptide as the amount of free amino acids excluding acetyl groups.

3. The reducing sugar was glucose in Examples 4 to 6, maltose in Example 7, and fructose in Example 8.

[Test example]

The enzyme solution contains rat plasma, rat liver (1.0 g) or rat kidney (1.0 g), and 0.05M) Lis-HCl buffer (p
1+8.010 mR) was used. After mixing 8, 0, and 150 μl of each substrate solution (250 μl and 0.05 M) with Lis-HCl buffer (pl), 100 μl of the enzyme solution was added and shaken at 37°C. Next, After adding methanol (1.5 mN), an internal standard substance was added and centrifuged. The supernatant was separated and Trp was quantified by liquid chromatography to determine its production rate. In this case, the rate of hydrolysis was determined by quantifying the amount of Acetyl-Ala that decreased after the reaction.

Table 6 Production rate of 7rp and hydrolysis rate of Acetyl-Ala Substrate Plasma Liver Kidney (μmol/min/ml Cumol/min/g)
(umol/min/g), it is possible to provide a comprehensive infusion solution that exhibits excellent nutritional effects and is highly bioavailable without causing any browning phenomenon.

Acetyl-Ala-Trp Acetyl-Trp-81a Acetyl-Trp Acetyl-Ala NC”1 1.59+0.27 NCNC NCNC NC1,53±0.03 1.31±0,11 0.05±0.01 0.12±6.31 2.63±0.77 a) NC means that the calculation could not be performed.

The results are shown in Table 6. Acetyl-Trp-Ala and Ace ty ITrp are hydrolyzed in the kidney, but Tr
The production rate of p is extremely slow. However, Acety
l-Ala-Trp is rapidly hydrolyzed in the liver and kidneys to generate Trp, which in turn generates Acetyl-Ala.
is also easily hydrolyzed.

〔Effect of the invention〕

Claims (2)

[Claims] (1) A reducing sugar-containing amino acid infusion composition containing an N-acylated dipeptide in which the C-terminus of the dipeptide is L-tryptophan and the N-terminus of the dipeptide is acylated. (2) Glycine and L-amino acids at the N-terminus of the dipeptide
Alanine, L-leucine, L-isoleucine, L-valine, L-threonine, L-serine, L-glutamic acid or L-aspartic acid are used, and the acyl group of the amino group of these amino acids is acetyl, propionyl, lactyl or The amino acid infusion composition according to claim 1, characterized in that it is selected from maleyl.