JPH07330583A - Liquid preparation containing free glutamic acid - Google Patents

Abstract

PURPOSE:To obtain a solution preparation which contains free glutamic acid and is useful as a nutrient supplement on invasion, such as infection, injury, ambustion or the like and it can be effectively absorbed from the cells of enteric mucosa, thus is effective as an enteral feeding or transfusion solution. CONSTITUTION:This preparation contains free glutamic acid, preferably in an amount of 20-30 mole % based on the total amino acids in the composition. Other nutrients than free glutamic acid are, for example, a variety of amino acids, peptides, proteins, carbohydrates, vitamins and the like. This preparation is preferably given to a patient enterally or intravenously at a dose of 800-2,000ml/day/adult.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a liquid preparation containing free glutamic acid. The present invention is particularly useful for nutritional support during invasiveness.

[0002]

2. Description of the Related Art As a method for supplying nutrition to patients with surgical diseases and various diseases, enteral nutritional agents and infusion agents are usually administered. Many of these substances are often mixed with amino acids as nutrients, and many amino acid compositions corresponding to various diseases have been reported.

In addition, there have been numerous reports on the effectiveness of glutamine on intestinal mucosal cells and systemic protein metabolism during invasion such as infection, trauma and burns. For example, glutamine taken up in intestinal mucosal cells is converted into glutamate by glutaminase. Then, it is converted into α-ketoglutarate and alanine by transaminase, and α-ketoglutarate is converted into energy in the intestinal tract. Alanine is also transported to the liver and used as an energy source. That is, glutamine incorporated into intestinal mucosal cells is useful as an energy source.

However, since free glutamine has a low solubility and is unstable in an aqueous solution, it cannot be incorporated into a convenient liquid nutrient or infusion.

[0005]

DISCLOSURE OF INVENTION Problems to be Solved by the Invention The present inventors have studied the efficacy of free glutamine and the formulation of a stable liquid composition at the time of invasion such as infection, trauma and burn. The addition of free glutamic acid to glutamine makes it possible to obtain a liquid formulation which is more effective than glutamine during invasion such as infection, trauma and burns, and which is stable as a enteral nutrient or infusion. I found it.

[0006]

The above-mentioned invention is as follows.

(1) A liquid preparation containing free glutamic acid.

(2) The liquid preparation according to the above (1), characterized in that the amount of free glutamic acid is 5 to 30% [molar ratio] of all amino acids.

(3) The liquid preparation according to the above (1) or (2), which efficiently supplies an energy substrate such as glutamic acid or alanine to the liver and intestinal tract.

(4) An enteral nutritional agent for invasive use, which comprises the liquid preparation described in (1) or (2) above.

(5) An infusion agent for insulting, which comprises the liquid preparation according to the above (1) or (2).

The present inventors administered a liquid preparation containing free glutamine or free glutamic acid to rats by enteral administration, and measured intestinal mucosal structure and barrier function, and blood amino acid concentrations in arteries and portal veins. . As a result, rats (hereinafter referred to as “G”) to which a liquid preparation containing free glutamine was enterally administered
LN group) and a rat (hereinafter referred to as GLU group) enterally administered with a liquid preparation containing free glutamic acid (henceforth referred to as GLU group), histological images of jejunum and ileum, and mesenteric lymph node (MLN)
No difference was observed in either bacterial culture or cumulative nitrogen equilibrium. In addition, the cumulative nitrogen balance was significantly better in the GLN group and the GLU group than in rats (hereinafter referred to as the non-addition group) which was enterally administered with a liquid preparation containing no glutamine and glutamic acid, and thus was used as an energy source for glutamic acid. Was shown to be effective.

On the other hand, when amino acids in blood were analyzed, the alanine concentration in the GLU group was significantly higher in the portal vein than in the GLN group and the non-added group, but in the arteries, all three groups were almost the same. I found it to be a value.

Nutrients absorbed in the intestinal mucosa are transported to the liver through the portal vein, metabolized in the liver, and partly transported from the liver to various places in the body through arteries. Glutamic acid taken up by intestinal mucosal cells is converted into α-ketoglutarate and alanine by transaminase, and α-ketoglutarate is converted into energy in the intestine. Alanine is also transported to the liver and used as an energy source.

That is, free glutamic acid administered enterally is used as an energy source for the intestinal tract like free glutamine, and at the same time, more glutamic acid is converted to alanine than glutamine, and the energy in the liver is increased. It was found to be used as a source.

[0016] Further, as a result of conducting the same test on the invasive rats, the invasive rats administered with the liquid preparation containing free glutamic acid utilized alanine more efficiently than the normal rats, particularly during the invasiveness such as infection, trauma and burn injury. It has been found to be effective in nutritional supplementation of.

In the present invention, it is possible to administer alanine instead of glutamine or glutamic acid, but this is not preferable because it cannot serve as an energy source in the intestinal tract.

In the present invention, the amount of free glutamic acid contained in the liquid preparation is 5 to 5 of all amino acids in the composition.
The content is 30% [molar ratio], and more preferably 20 to 30% [molar ratio]. When it is less than 5% [molar ratio], the conversion efficiency to alanine is poor, and when it is 30% [molar ratio] or more, the amino acid balance is disturbed, which is not preferable.

In the liquid preparation of the present invention, the nutrient source to be added in addition to free glutamic acid is not limited at all, and various commonly used amino acids, peptides, proteins, sugars, vitamins, lipids and the like can be used. .

The liquid preparation of the present invention can be used as an enteral nutrient, and the nutrient source to be incorporated in addition to free glutamic acid is not limited as described above, and a known composition can be used. The specific composition as an enteral nutrient is shown below.

(In 500 ml of enteral nutritional supplement) L-leucine 1.5-3 (g) L-isoleucine 0.5-1.5 (g) L-valine 0.5-1.5 (g) L- Lysine / malate 1.5- 3 (g) L-threonine 0.5-1.5 (g) L-tryptophan 0.1-1 (g) L-methionine 0.5-1 (g) L- Phenylalanine 1-2 (g) L-cystine 0-0.5 (g) L-tyrosine 0-0.5 (g)

L-arginine 2-3 (g) L-histidine 0.5-1.5 (g) L-alanine 1-2 (g) L-proline 1.5-3 (g) L-serine 0. 5-1.5 (g) aminoacetic acid 2-3.5 (g) L-aspartic acid 0-0.5 (g) L-glutamic acid 1.8-10.8 (g) NaCl 0.4-0.0. 5 (g) Na citrate 0.5-1 (g)

[0023] _{KCl 0.5~ 1 (g) MgCl 2} · 6H 2 O 0.5~ 1 (g) glycerophosphate Ca 1.5~ 2 (g) gluconate Fe 25 ~ 30 (mg) ZnSO 4 · 7H ₂ O 5 to 10 (mg) CuSO ₄ .5H ₂ O 0.5 to 1 (mg) MgSO ₄ .7H ₂ O 4 to 5 (mg) Dextrin 50 to 100 (g) Soybean oil 3 to 8 (g) Vitamin A 500-700 (IU)

Vitamin D 50 to 70 (IU) Vitamin B ₁ 0.5 to 1 (mg) Vitamin B ₂ 0.5 to 1 (mg) Vitamin B ₆ 0.5 to 1 (mg) Vitamin C 50 to 200 ( mg) Vitamin K 100 to 500 (μg) Vitamin E 10 to 25 (mg) Folic acid 50 to 100 (μg) Pantothenic acid 10 to 15 (mg) Vitamin B ₁₂ 1 to 1.5 (μg) Biotin 25 to 50 (mg) )

In the present invention, glutamic acid is taken into the intestinal mucosal cells from the gastrointestinal lumen through the brush border membrane when ingested or from the arterial blood through the basement membrane and cell-side membrane when transfused. As described above, the nutrient source to be blended in addition to free glutamic acid is not limited at all, and a known composition can be used. The specific composition as an infusion solution is shown below.

(In 500 ml of infusion solution) L-leucine 1.5-3 (g) L-isoleucine 0.5-1.5 (g) L-valine 0.5-1.5 (g) L-lysine. Malate 1.5 to 3 (g) L-threonine 0.5 to 1.5 (g) L-tryptophan 0.1 to 1 (g) L-methionine 0.5 to 1 (g) L-phenylalanine 1 ~ 2 (g) L-cystine 0-0.5 (g)

L-tyrosine 0-0.5 (g) L-arginine 2-3 (g) L-histidine 0.5-1.5 (g) L-alanine 1-2 (g) L-proline 1. 5-3 (g) L-serine 0.5-1.5 (g) aminoacetic acid 2-3.5 (g) L-aspartic acid 0-0.5 (g) L-glutamic acid 1.8-10. 8 (g) Glucose 50-100 (g)

Potassium chloride 0.5-1 (g) Magnesium sulphate 0.2-0.5 (g) Magnesium chloride 0.03-0.06 (g) Calcium gluconate 0.5-1 (g) Phosphoric acid Potassium dihydrogen 0.4 to 0.6 (g) Sodium lactate solution 2 to 5 (g) Zinc sulfate 2 to 4 (mg) Acetic acid 0.1 to 0.5 (g)

The method for producing the liquid preparation of the present invention is not particularly limited, and there is a method in which various components such as glutamic acid are dissolved in water or a protein or peptide is treated with an enzyme to obtain a preparation containing glutamic acid. The obtained liquid preparation can be sterilized by autoclave sterilization.

The above-mentioned liquid preparation of the present invention is 400-300 per day for an adult by enteral administration or intravenous administration.
0 ml, preferably 800-2000 ml is administered.

[0031]

EXAMPLES The present invention will be described in more detail below with reference to examples.

Example A liquid preparation containing glutamic acid according to the present invention was prepared as follows. Liquid A-1 in which the following components were mixed was placed in a 500 ml bag and
Enclose 50 ml and autoclave sterilize (100 ° C, 15
Minutes) Next, A- which is a mixture of the following components
250 ml of the 2nd liquid was sealed in a 250 ml bag and sterilized by autoclave (100 ° C., 15 minutes). A-1 obtained
Solution and Solution A-2 are used by mixing in a bag containing Solution A-1 immediately before administration.

Liquid A-1 (12.78% amino acid 250 ml) L-leucine 2.063 (g) L-isoleucine 1.083 (g) L-valine 1.250 (g) L-lysine malate 2 .163 (g) L-threonine 0.915 (g) L-tryptophan 0.340 (g) L-methionine 0.785 (g) L-phenylalanine 1.768 (g)

L-cystine 0.040 (g) L-tyrosine 0.105 (g) L-arginine 2.233 (g) L-histidine 0.950 (g) L-alanine 1.490 (g) L- Proline 1.923 (g) L-serine 0.845 (g) Aminoacetic acid 2.843 (g) L-Aspartic acid 0.365 (g) L-Glutamic acid 10.805 (g)

NaCl 0.430 (g) Na citrate 0.870 (g) KCl 0.715 (g) MgCl ₂ .6H ₂ O 0.900 (g) Glycerophosphate Ca 1.963 (g) Fe gluconate 29.25 (mg) ZnSO ₄ .7H ₂ O 8.75 (mg) CuSO ₄ .5H ₂ O 0.98 (mg) MgSO ₄ .7H ₂ O 4.50 (mg)

Solution A (250 ml) Dextrin 80.45 (g) Soybean oil 5.56 (g) Vitamin A 625 (IU) Vitamin D 62.5 (IU) Vitamin B ₁ 0.75 (mg) Vitamin B ₂ 0.75 (mg) Vitamin B ₆ 0.75 (mg)

Vitamin C 125 (mg) Vitamin K 312.5 (μg) Vitamin E 18.75 (mg) Folic acid 75 (μg) Pantothenic acid 12 (mg) Vitamin B ₁₂ 1.25 (μg) Biotin 31.25 ( mg)

Solution A-1 + Solution A-2 (500 ml) Total calorific value 499.72 (kcal) Nitrogen dose 1.666 (g) Total calorie / ml 1

Comparative Example For comparison, a liquid preparation containing glutamine was prepared as follows. Liquid B-1 in which the following components are mixed is placed in a 500 ml bag for 250 m.
It was then sealed and autoclaved (100 ° C., 15 minutes). Next, 250 ml of the B-2 solution mixed with the respective constituents shown below was sealed in a 250 ml bag and autoclaved (100 ° C., 15 minutes). Obtained B-1 solution, B
Solution-2 is used by mixing it with a bag containing Solution B-1 immediately before administration.

Solution B-1 (10.23% amino acid 250 ml) L-leucine 1.655 (g) L-isoleucine 0.870 (g) L-valine 1.003 (g) L-lysine malate 1 0.733 (g) L-threonine 0.733 (g) L-tryptophan 0.273 (g) L-methionine 0.630 (g) L-phenylalanine 1.418 (g)

L-cystine 0.025 (g) L-tyrosine 0.085 (g) L-arginine 1.790 (g) L-histidine 0.760 (g) L-alanine 1.195 (g) L- Proline 1.543 (g) L-serine 0.678 (g) Aminoacetic acid 2.280 (g) L-Aspartic acid 0.293 (g) L-Glutamine 8.608 (g)

NaCl 0.430 (g) Na citrate 0.870 (g) KCl 0.715 (g) MgCl ₂ .6H ₂ O 0.900 (g) Glycerophosphate Ca 1.963 (g) Fe gluconate 29.25 (mg) ZnSO ₄ .7H ₂ O 8.75 (mg) CuSO ₄ .5H ₂ O 0.98 (mg) MgSO ₄ .7H ₂ O 4.50 (mg)

Solution B-2 (250 ml) Dextrin 85.98 (g) Soybean oil 5.98 (g) Vitamin A 625 (IU) Vitamin D 62.5 (IU) Vitamin B ₁ 0.75 (mg) Vitamin B ₂ 0.75 (mg) Vitamin B ₆ 0.75 (mg)

Vitamin C 125 (mg) Vitamin K 312.5 (μg) Vitamin E 18.75 (mg) Folic acid 75 (μg) Pantothenic acid 12 (mg) Vitamin B ₁₂ 1.25 (μg) Biotin 31.25 ( mg)

Solution B-1 + Solution B-2 (500 ml) Total heat quantity 500.06 (kcal) Nitrogen dose 1.666 (g) Total heat quantity / ml 1

(Non-addition Example) For comparison, a liquid preparation containing neither glutamine nor glutamic acid was prepared as follows. A C-1 solution containing the components shown below was mixed with 500
250 ml was sealed in a ml bag and autoclaved (100 ° C., 15 minutes). Next, 250 ml of the C-2 liquid mixed with the components shown below is placed in a 250 ml bag.
It was sealed and autoclaved (100 ° C., 15 minutes). The obtained C-1 solution and C-2 solution were treated with C-
Mix in a bag containing 1 liquid before use.

Solution C-1 (10.23% amino acid 250 ml) L-leucine 2.740 (g) L-isoleucine 1.438 (g) L-valine 1.663 (g) L-lysine malate 2 .870 (g) L-threonine 1.213 (g) L-tryptophan 0.450 (g) L-methionine 1.043 (g) L-phenylalanine 2.345 (g)

L-cystine 0.005 (g) L-tyrosine 0.138 (g) L-arginine 2.963 (g) L-histidine 1.260 (g) L-alanine 1.978 (g) L- Proline 2.555 (g) L-serine 1.123 (g) Aminoacetic acid 3.775 (g) L-Aspartic acid 0.488 (g)

NaCl 0.430 (g) Na citrate 0.870 (g) KCl 0.715 (g) MgCl ₂ .6H ₂ O 0.900 (g) Glycerophosphate Ca 1.963 (g) Fe gluconate 29.25 (mg) ZnSO ₄ .7H ₂ O 8.75 (mg) CuSO ₄ .5H ₂ O 0.98 (mg) MgSO ₄ .7H ₂ O 4.50 (mg)

C-2 solution (250 ml) Dextrin 83.80 (g) Soybean oil 5.80 (g) Vitamin A 625 (IU) Vitamin D 62.5 (IU) Vitamin B ₁ 0.75 (mg) Vitamin B ₂ 0.75 (mg) Vitamin B ₆ 0.75 (mg)

Vitamin C 125 (mg) Vitamin K 312.5 (μg) Vitamin E 18.75 (mg) Folic acid 75 (μg) Pantothenic acid 12 (mg) Vitamin B ₁₂ 1.25 (μg) Biotin 31.25 ( mg)

C-1 liquid + C-2 liquid (500 m
l) Total calorie 499.8 (kcal) Nitrogen dose 1.666 (g) Total calorie / ml 1

(Test Example 1) A SD rat (male, 6 weeks old) having a body weight of about 250 g was fitted with a catheter in the duodenum according to a conventional method under ether anesthesia to secure an enteral administration line. At the same time, a burn was created on the shaved back using an electric iron (300 ° C). The burned area was 30% of the body surface area.

Immediately after preparation of the burn, lactated Ringer's solution (Sollacto, manufactured by Terumo Corp.) was enterally administered (300 ml / k).
(g / day) for 12 hours, the rats were divided into 3 groups, and the liquid preparations of Examples, Comparative Examples and non-addition examples were administered for 3 days (27
(0 ml / kg / day) continuous enteral administration.

After the administration was completed, the small intestine and lymph node (MLN) were collected, histological examination of the jejunum and ileum and bacterial culture of MLN were performed, the amino acid concentrations of aortic blood and portal vein blood, and urinary nitrogen were also examined. The quantity was measured.

In this test example, histological examination was carried out by hematoxylin-eosin staining according to a conventional method, and MLN
Of homogenized bacterial culture of TSA medium at 37 ℃ 24
I went on time.

The results of each are shown below. No difference was observed in the histological images of jejunum and ileum between the example and the comparative example. Even in bacterial culture of MLN, 2622 ±
1254 [CFU / gMLN], 3104 ± 1 in Comparative Example
865 [CFU / gMLN], 8512 ± 9 in the additive-free example
It was 86 [CFU / gMLN], and the example was better than the comparative example and the non-addition example. Also in the cumulative nitrogen equilibrium, the value of -69 ± 213 [mg / kg / 4 days] in the non-added example was 388 ± 220 [mg / k] in the example.
g / 4 days], 473 ± 349 [mg / kg / 4 in Comparative Example
Day], the effect of addition was recognized, and the example and the comparative example were equivalent.

However, at the amino acid concentration, the alanine concentration was 1433 ± 77 in the example in portal blood.
[Nmol / ml], 1035 ± 95 [nmo in Comparative Example
1 / ml], which was significantly higher in the Example than in the Comparative Example, but 586 ± 19 [nmo] in the Example in arterial blood.
1 / ml], 654 ± 60 [nmol / ml] in Comparative Example
It was almost the same value. From this, it was shown that enterally administered glutamic acid was utilized more efficiently than glutamine in the intestinal tract and liver.

Test Example 2 In order to confirm the availability of glutamic acid as an energy source, the same test as in Test Example 1 was carried out on non-invasive normal rats. As a result, the concentration of alanine in portal vein plasma was 1440 ± 55 [nm in the example.
ol / ml], 977 ± 51 [nmol / m in Comparative Example
1], it was shown that glutamic acid was well metabolized by intestinal mucosal cells as in the burned rat with invasiveness of Test Example 1. However, the alanine concentration in the aortic plasma was 752 ± 47 [nmol / ml] in the example and 569 ± 27 [nmol / ml] in the comparative example. Showed high availability of alanine.

That is, glutamic acid is metabolized in intestinal mucosal cells and used as an energy source even under normal conditions.
It can be said that it is a more efficient energy source in invasive rats.

[0061]

INDUSTRIAL APPLICABILITY The liquid preparation containing free glutamic acid of the present invention can be added in a more stable and larger amount than the liquid preparation containing free glutamine, and glutamic acid is efficiently metabolized in the intestinal mucosa to produce metabolites. Since α-ketoglutarate is carried in the intestinal tract and alanine is carried to the liver and used efficiently as an energy source, it is effective for nutritional supplementation.

The liquid preparation containing free glutamic acid of the present invention is mainly administered as an enteral nutritional agent and an infusion agent.
Furthermore, the liquid preparation containing the free glutamic acid of the present invention supplies energy to the intestinal tract and liver even when glutamic acid is normal, but at the time of invasion such as burn injury,
Since it is used more efficiently, it is particularly effective for nutritional supplementation during invasion.

Claims (5)

[Claims] 1. A liquid preparation containing free glutamic acid. 2. The liquid preparation according to claim 1, wherein the amount of free glutamic acid is 5 to 30% [molar ratio] of all amino acids. 3. The liquid preparation according to claim 1, which supplies an energy substrate to the liver and the intestinal tract. 4. An enteral nutritional agent for invasive use, which comprises the liquid preparation according to claim 1. 5. An infusion solution for invasion, which comprises the liquid preparation according to claim 1.