JPH11302164A - Amino acid composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a safe amino acid-containing transfusion capable of supplying a sufficient quantity of glutamine and having well-balanced compounding quantities of other amino acids, excellent in supplementing amino acids and having excellent storage stability and solubility. SOLUTION: This composition is such as to be in the form of constituting a transfusion preparation before administration by contacting, when to be used, solid ingredients dissolvable when to be used, with a liquid so as to dissolve these solid ingredients when to be used. The concentration of each ingredient in the transfusion composition when to be administered is as follows; 2-16 g/l for isoleucine; 2-20 g/l for leucine; 4-25 g/l for valine; 1-25g/l for lysine; forl-8 g/l for methionine; 1-11 g/l for phenylalanine; 1-18 g/l for threonine; 1-8 g/l for tryptophan; 1-10 g/l for histidine; 0-10 g/l for cysteine; 0.1-10 g/l for tyrosine; 0-50g/l for alanine; 1-25 g/l for arginine; 0-6 g/l aspartic acid; 0-10g/l for glutamic acid; 0-25 g/l for glycine; 0-25 g/l for proline; 0-15 g/l for serine; and 10-60 g/l for glutamine. It is preferable that as at least the glutamine out of the above amlno acids, its lyophilized product is used.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a glutamine-containing nutrient solution preparation, and more particularly to a glutamine-containing nutrient solution containing specific amounts of various amino acids with respect to the glutamine in addition to glutamine. The present invention relates to a glutamine-containing nutrient solution formulation suitable for use by dissolving in a physiological dissolving solution. In another aspect, the present invention provides a glutamine-containing nutritional supplement suitable for use in pathological conditions in a surgical invasion following a burn, trauma, surgery, etc. or an acute infection resulting from microbial infections such as bacteria, viruses and the like. It relates to a liquid preparation.

[0002]

2. Description of the Related Art Patients who are unable or unable to take nutrition orally due to meals or have a shortage of nutrients in the living body, and need to replenish the nutrients urgently. Nutrition management has become possible and can be achieved to a certain extent by supplementing such patients with complete parenteral nutrition. Thus, intravenous amino acid nutritional infusion is
Despite the need to take appropriate levels of amino acids, proteins, etc. for nutritional supplementation during various diseases or before and after surgery, it is not possible to eat orally,
Alternatively, it is widely used for nutritional management when its intake is insufficient or it is necessary to replenish it urgently, and its effect has been recognized in the treatment. In recent years, the amino acid composition in nutrient infusions has been actively studied, and amino acid preparations for various diseases have been developed not only for nutritional supplementation but also for alleviation / improvement and treatment of disease states. I have. Until now, these amino acid nutritional infusions marketed in Japan contain various essential amino acids, but none contain glutamine at present.

[0003] Glutamine is not one of the essential amino acids, and is a non-essential amino acid that is easily abundantly synthesized in the body from other amino acids without ingestion from the body and is abundant in the body. It is considered to be due to the fact that it is hardly soluble and, in addition, its chemical stability is so poor that glutamine cannot be formulated. Glutamine is not only the most abundant in the amino acid pool and free amino acids in the blood of skeletal muscle in vivo, but when administered, glutamine suppresses the breakdown of muscle proteins, activates immune function, and makes the intestinal tract healthy. It has been found that by maintaining and maintaining it, it has the effect of preventing complications and promoting patient recovery, and recently its nutritional function in vivo and unique physiological activities have been elucidated. However, its use as an infusion is attracting attention.

[0004] Glutamine is almost entirely synthesized in the body under normal conditions, and it is said that the amount consumed in the diet is negligible compared to the amount consumed in the body. No need for glutamine. However, once invasion or the like is added to a living body, glutamine consumption is rapidly increased, and a relative glutamine deficiency state is caused. For example, burns,
After trauma, surgery, etc., as a raw material for protein synthesis,
It is also believed that the use of glutamine as an energy source for cells such as immune cells and as various materials for repairing wounds and damaged tissues / cells is enhanced. Biological reactions caused by various bacterial factors, such as infectious diseases, are also thought to increase glutamine demand.

[0005]

As pointed out above, glutamine is hardly soluble by itself, is unstable even when dissolved, and has a problem that it is easily decomposed by heat, acid and alkali. In particular, when administered intravenously as an infusion, the generation of such ammonia becomes a serious defect. In order to avoid such problems and to be able to administer a sufficient amount of glutamine intravenously as an infusion, various measures are required. In recent years, in the formulation, formulations containing dipeptide derivatives such as glycyl-glutamine (Gly-Gln) and alanyl-glutamine (Ala-Gln) have been developed in addition to glutamine. Is immediately hydrolyzed by peptidase and decomposed into the respective amino acids. Therefore, when administered as an infusion, an imbalance occurs between the formulated amino acids in the living body, and it is difficult to achieve an optimal infusion composition, which is not always preferable. That is, glutamine is 30% to 50% of the total amount of free amino acids in the whole body
Because it is the most abundant among amino acids, when it is used in a transfusion preparation containing 10% of normal amino acids, it must contain at least about 3% of glutamine (that is, at least about 30% of the total amino acids). Therefore, if this is to be achieved by blending a dipeptide derivative, the other amino acids in the dipeptide derivative paired with glutamine are inevitably administered in excess, resulting in an amino acid in the entire amino acid. This will result in a balanced replenishment. This can also cause significant problems in terms of nitrogen content in the infusion.

As described above, an infusion for replenishing a living body with glutamine is not suitable for surgical invasion after burns, trauma, surgery, etc., or acute infectious diseases caused by microbial infections such as bacteria and viruses. In such a case, the amino acids to be administered need to be balanced. Therefore, a sufficient amount of glutamine can be supplied as a compounded amino acid composition, and the compounding amount of other amino acids also has such a function.
It is strongly desired to provide one suitable for use. On the other hand, as a technology that has made it possible to use glutamine safely and stably as an infusion, there is a glutamine-containing nutrient solution by the same applicant as the present application (JP-A-9-29456).
No. 5). In this technique, glutamine is formulated in a lyophilized state separately from the liquid component of the infusion, and the solid component and the liquid component are brought into contact with each other before administration to reconstitute the infusion. In such reconstituted infusion preparations, it is necessary to rapidly and safely dissolve the components completely. This has the problem that, for example, when it takes too much time to dissolve the components, the unstable components may be decomposed or the urgent use cannot be made. In addition, if administration is started in an incompletely dissolved state, there arises a problem that, when administered by intravenous injection or the like, a shock is caused to the living body, and the component concentration and the like differ between the start and end of administration. Further, since it is practically difficult to perform such dissolution treatment as heating or vigorous stirring, it is necessary that the dissolution treatment can be performed promptly and smoothly only by mixing them at room temperature.

[0007] Accordingly, there is a need to provide an infusion solution that can achieve rapid and complete reconstitution of components and has a desired amino acid composition. Particularly, a sufficient amount of the compound is used in a stable form at the time of use for a living body that is in a pathological state such as a surgical invasion after burns, trauma, surgery, or an acute infection caused by microbial infection such as bacteria and viruses. There is a need to provide an infusion preparation that can supply glutamine and amino acids other than glutamine in an amount sufficient for such living bodies, and that can be used more safely, reliably, and easily.

[0008]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, at a specific compounding ratio and amount, amino acids excellent in nutritional effects have been contained and a sufficient amount has been obtained. By incorporating glutamine, a glutamine or the like is dissolved in a liquid component prior to administration and a reconstituted form of the preparation, for example, by using a solid component obtained by freeze-drying, simple and quick, In addition, they have found that they can obtain the required action and effect, and that they can be used stably for a long time, and that they can obtain an infusion that is uniform and safe to use after preparation. As a result, the present invention has been completed. The present invention dissolves a solid amino acid composition composed of glutamine and other amino acids and containing a required amount of each which can be adapted to a required purpose and use, in water or an aqueous solution containing an electrolyte, a saccharide, and the like. The dissolution operation is performed aseptically at the time of use.

That is, the present invention provides (1) isoleucine 2 to 16 g / l, leucine 2 to 20 g / l, valine 4 to 25 g / l, lysine 1 to 25 g / l, methionine 1 to 8 g / l l, phenylalanine 1-11 g / l, threonine 1-18 g / l, tryptophan 1-8 g / l, histidine 1-10 g / l, cysteine 0-10 g / l, tyrosine 0.1-10 g / l, Alanine 0-50 g / l, arginine 1-25 g / l, aspartic acid 0-6 g / l, glutamic acid 0-10 g / l, glycine 0-25 g / l, proline 0-25 g / l, serine A solid amino acid composition containing each amino acid in an amount to give 0-15 g / l and glutamine 10-60 g / l in the infusion composition at the time of administration; (2) isoleucine 5-10 g / l, leucine 8-16 g / l, valine 5-20 g / l, lysine 5-15 g / l, methionine 3-6 g / l, phenylalanine 3-10 g / l, threonine 3-10 g / l l, tryptophan 1-6 g / l, histidine 2-9 g / l, system In 0.1-5 g / l, tyrosine 0.2-3 g / l, alanine 0.1-10 g / l, arginine 5-15 g / l, aspartic acid 0.4-4 g / l, glutamic acid 0.1-6 g / l, glycine 0.1 to 14 g / l, proline 1 to 10 g / l, serine 1 to 10 g / l, and glutamine 15 to 50 g / l are provided in the infusion composition at the time of administration. (3) isoleucine 6-8 g / l, leucine 10-14 g / l, valine 6-10 g / l, lysine 8-11 g / l, Methionine 3-5 g / l, phenylalanine 5-8 g / l, threonine 4-8 g / l, tryptophan 1-2 g / l, histidine 2-7 g / l, cysteine 0.1-2 g / l, tyrosine 0.2 ~ 1 g / l, alanine 0.2 ~ 5 g / l, arginine 7 ~ 13 g / l, aspartic acid 0.5 ~ 2 g / l, glutamic acid 0.2 ~ 2 g / l, glycine 1 ~ 13 g / l, proline 2 ~ 7 g / l, serine 1.5-7 g / l and glutamine 15-40 g / l In an amount to provide in the composition, the characterized by containing each amino acid (1) solid acid composition according;

(4) Glutamine is a freeze-dried product, or cysteine, tryptophan, tyrosine,
The solid amino acid composition according to any one of the above (1) to (3), wherein the amino acid selected from the group consisting of glutamic acid and aspartic acid and glutamine are freeze-dried products; The above (1) to (1) to (1), wherein the dried glutamine is freeze-dried in the presence of other substances together with glutamine in a weight ratio to glutamine of 0.8 or more.
(6) The solid amino acid composition according to any one of (1) to (5), and the solid amino acid composition according to any one of the above (1) to (5) and water or an electrolyte, a saccharide, an amino acid, or the like. A combination infusion preparation comprising an aqueous solution containing a substance selected from the group, wherein the preparation and the preparation form a set; (7) (a) glutamine; and (b) other than glutamine. (8) The infusion preparation according to the above (6), wherein a weight ratio to a substance selected from the group consisting of amino acids, saccharides, electrolytes, and vitamins is 0.8 or more; and (8) the above (1) to (5). A method for producing an amino acid-containing preparation, comprising dissolving the solid amino acid composition according to any one of the above) in water or an aqueous solution containing one selected from the group consisting of electrolytes, saccharides, amino acids and the like. provide.

In another aspect, the present invention further provides (9) a container containing the solid amino acid composition according to any one of the above (1) to (5) aseptically, and water or an electrolyte. , A container containing an aqueous solution containing a solution selected from the group consisting of sugars, amino acids, and the like, aseptically connected to each other, so that both containers can communicate with each other,
(10) A method for producing an amino acid-containing preparation characterized by comprising an infusion preparation prior to administration; (10) an amino acid selected from the group consisting of cysteine and tryptophan and glutamine as a lyophilized product. The solid amino acid composition according to any one of the above (1) to (5); and (11) The solid amino acid composition according to any one of the above (1) to (5) is sterilized. A container housed in
Water or an electrolyte, a saccharide, a container containing aseptically containing an aqueous solution containing one selected from the group consisting of amino acids, etc., further aseptically containing a container containing fat emulsion aseptically, Provided is a method for producing an amino acid-containing preparation, characterized by allowing both containers to communicate with each other when in use.

According to the present invention, there is further provided (12) a solid component dissolvable at the time of use and a liquid for dissolving the solid component at the time of use, which are brought into contact with each other at the time of use to constitute an infusion preparation before administration. The amount of each amino acid in the amount in the infusion composition at the time of administration is determined by the following composition: isoleucine 2-16 g / l, leucine 2-20 g / l, valine 4-25 g / l, lysine 1-25 g / l, methionine 1-8 g / l, phenylalanine 1-11 g / l, threonine 1-18 g / l, tryptophan 1-8 g / l, histidine 1-10 g / l l, cysteine 0-10 g / l, tyrosine 0.1-10 g / l, alanine 0-50 g / l, arginine 1-25 g / l, aspartic acid 0-6 g / l, glutamic acid 0-10 g / l Glycine 0-25 g / l, proline 0-25 g / l, serine 0-15 g / l and glutamine 10-60 g / l, of which at least glutamine is a lyophilized product and Dissolvable (13) a freeze-dried glutamine, which is provided as a solid component and is freeze-dried in the presence of glutamine and other substances together with glutamine in a weight ratio to glutamine of 0.8 or more; (1)
(14) The amino acid-containing infusion preparation according to (2), wherein (14) the freeze-dried glutamine is freeze-dried in the presence of glutamine and another substance in a weight ratio to glutamine of 0.8 to 3 in combination with glutamine.
(15) The lyophilized glutamine is lyophilized by coexisting with glutamine and another substance in a weight ratio to glutamine of 1 to 25 and lyophilized glutamine according to (2) or (13). (12)
(16) an amino acid selected from the group consisting of cysteine, tryptophan, tyrosine, glutamic acid and aspartic acid and glutamine, which are freeze-dried and soluble at the time of use; (17) An amino acid-containing infusion preparation according to any one of the above (12) to (15), which is contained as a solid component; (17) an amino acid selected from the group consisting of cysteine and tryptophan An amino acid-containing infusion preparation according to any one of the above (12) to (16), wherein glutamine is a freeze-dried product and is contained as a solid component that can be dissolved at the time of use; (18) As the solid component that can be dissolved at the time of use, a component selected from the group consisting of sugars and inorganic salts is further contained. Above, characterized in that (12) - (1
7) the amino acid-containing infusion preparation according to any one of the above;

(19) The liquid characterized in that the liquid for dissolving the solid component at the time of use is water or an aqueous solution containing one selected from the group consisting of electrolytes, saccharides, amino acids and the like. 12) The amino acid-containing infusion preparation according to any one of (18); (20) a liquid for dissolving the solid component at the time of use,
Isoleucine, leucine, valine, lysine, methionine, phenylalanine, threonine, tryptophan,
An amino acid-containing infusion preparation according to the above (19), which is an aqueous solution containing an amino acid selected from the group consisting of histidine, cysteine, tyrosine, alanine, arginine, aspartic acid, glutamic acid, glycine, proline and serine; (21) A liquid for dissolving the solid component at the time of use,
An aqueous solution containing an amino acid selected from the group consisting of isoleucine, leucine, valine, lysine, methionine, phenylalanine, threonine, histidine, tyrosine, alanine, arginine, aspartic acid, glutamic acid, glycine, proline and serine. The amino acid-containing infusion preparation according to the above (19) or (20), and (22) a liquid for dissolving the solid component at the time of use,
(19) to () wherein the aqueous solution contains an amino acid selected from the group consisting of isoleucine, leucine, valine, lysine, methionine, phenylalanine, threonine, histidine, alanine, arginine, glycine, proline and serine. 21) An amino acid-containing infusion preparation according to any one of the above 21).

In a more specific embodiment, the present invention provides (23) isoleucine 2-16 g / l, leucine 2-20 g / l, valine 4-25 g / l, lysine 1-25 g / l, methionine 1 -8 g / l, phenylalanine 1-11 g / l, threonine 1-18 g / l, tryptophan 1-8 g / l, histidine 1-10 g / l, cysteine 0-10 g / l, tyrosine 0.1-10 g / l, alanine 0-50 g / l, arginine 1-25 g / l, aspartic acid 0-6 g / l, glutamic acid 0-10 g / l, glycine 0-25 g / l, proline 0-25 g / 24, isoleucine; an amino acid infusion composition characterized by containing each amino acid in an amount to give in the infusion composition at the time of administration, 0-15 g / l of serine and 10-60 g / l of glutamine; 5 ~ 10 g / l, leucine 8 ~ 16 g / l, valine 5 ~ 20 g / l, lysine 5 ~ 15 g / l, methionine 3 ~ 6 g / l, phenylalanine 3 ~ 10 g / l, threonine 3 ~ 10 g / l, tryptophan 1-6 g / l, histidine 2 ~ 9 g / l, cysteine 0.1 ~ 5 g / l, tyrosine 0.2 ~ 3 g / l, alanine 0.1 ~ 10 g / l, arginine 5 ~ 15 g / l, aspartic acid 0.4 ~ 4 g / l, glutamic acid 0.1 ~ 6 g / l, glycine 0.1-14 g / l, proline 1-10 g / l, serine 1-10 g / l and glutamine 15-50 g / l in the amount given in the infusion composition at the time of administration. The amino acid infusion composition according to the above (23), which comprises an amino acid; (25) isoleucine 6 to 8 g / l, leucine 10 to 14 g / l, valine 6 to 10 g / l, lysine 8 to 11 g / l, methionine 3-5 g / l, phenylalanine 5-8 g / l, threonine 4-8 g / l, tryptophan 1-2 g / l, histidine 2-7 g / l, cysteine 0.1-2 g / l, tyrosine 0.2-1 g / l, alanine 0.2-5 g / l, arginine 7-13 g / l, aspartic acid 0.5-2 g / l, glutamic acid 0.2-2 g / l, glycine 1-13 g / l, proline 2-7 g / l, serine 1.5-7 g / l and glutamine 15-40 The amino acid infusion composition according to the above (23), wherein each amino acid is contained in an amount to give g / l in the infusion composition at the time of administration;

(26) It is characterized in that it is used for pathological conditions such as surgical invasion after burns, trauma, surgery, etc. or acute infections caused by microbial infections such as bacteria and viruses. (27) suppression of muscle protein breakdown, promotion of protein synthesis, promotion of nucleic acid synthesis in immune cells, activation of immune cells, neutrophils Enhances bactericidal activity, suppresses intestinal mucosal atrophy, maintains intestinal mucosal structure, suppresses intestinal mucosal permeability, promotes absorption of sodium and water, improves nutrient absorption, promotes liver regeneration, suppresses fatty liver, inhibits glutathione production Is used for the purpose of obtaining an administration effect selected from the group consisting of promotion, suppression of in vivo peroxidation reaction, improvement of nitrogen balance, promotion of wound healing, suppression of pancreatic atrophy, and promotion of renal arginine production. And (28) a burn, trauma, surgery, acute infection, chronic infection,
Selected from the group consisting of severe catabolic diseases such as bone marrow transplantation, progressive malignancies, intestinal dysfunction (including inflammatory bowel disease, infectious enteritis, short bowel syndrome, after chemotherapy or radiation therapy) and immunodeficiency syndrome The composition according to any one of the above (23) to (25), which is used for adaptation.

[0016]

According to the present invention, there is provided an infusion preparation containing each amino acid in a specific amount. Although the preparation makes it possible to supply glutamine in a certain condition in an amount sufficient to meet the demands of the living body, it can avoid the danger of unnecessarily administering an excess of amino acids. Things. In a pathological condition, it is meaningful to supply a sufficient amount of each amino acid because metabolic function is impaired or resistance is lost. That can cause serious problems. In short, it is necessary to be able to administer necessary amounts of each amino acid to a living body in a well-balanced manner, and the infusion preparation of the present invention meets such an object. In the present invention, the amount sufficient to satisfy the amount required by the living body, when the infusion of the present invention is administered by drip or intravenous administration, the amino acid concentration is closer to the level observed in normal human blood or human milk or An amount can be meant that is capable of restoring and / or maintaining the concentration. Further, in the present invention, the amount sufficient to satisfy the amount required by the living body means an amount capable of restoring and / or maintaining the amino acid concentration at the target site to that of a healthy human. You can also. Similarly, in the present invention, the well-balanced amount of each amino acid can be an amount showing each amino acid concentration balance that is observed in healthy human blood or an amount showing each amino acid concentration balance close to it. For example, the amount can be within a range of about ± 100% of the balance of each amino acid concentration observed in healthy human blood.

According to the present invention, a solid component dissolvable at the time of use and a liquid for dissolving the solid component at the time of use are brought into contact with each other at the time of use to form an infusion preparation before administration. The formulation of, when viewed in the amount in the infusion composition at the time of administration, the ratio of the amount of each amino acid is included in a specific preferred amount, at least glutamine of the amino acids contained is a lyophilized product and By being provided as a solid component that can be dissolved at the time of use, it can be used for a long period of time as a pharmaceutical product with peace of mind, and can constitute an infusion solution that can be administered quickly and safely. It is in such a form. Glutamine used and blended especially as a freeze-dried product is glutamine together with other substances (preferably water-soluble compounds, such as amino acids such as alanine, glycine, and arginine, sugars such as glucose, and inorganic salts such as sodium chloride. ) By weight ratio to glutamine of 0.8 or more, preferably 1 to 1.2 or more, more preferably
It is freeze-dried in the presence of 1 to 25, more preferably 1 to 5. In the present invention, among the solid components that can be dissolved at the time of use, preferably those containing an amino acid selected from the group consisting of cysteine, tryptophan, tyrosine, glutamic acid and aspartic acid and glutamine as a lyophilized product. Particularly preferably, those containing an amino acid selected from the group consisting of cysteine and tryptophan and glutamine as a lyophilized product are included.

In a more preferred embodiment, the solid component soluble in use contains glutamine and cysteine and / or tryptophan as a lyophilized product. In a more preferred embodiment, glutamine and cysteine, tryptophan, Those containing tyrosine, glutamic acid and / or aspartic acid as a freeze-dried product may be mentioned. In addition, in the present invention, the solid components that can be dissolved at the time of use include isoleucine, leucine, valine, lysine, methionine, phenylalanine, threonine, tryptophan, histidine, cysteine, tyrosine, alanine, arginine, aspartic acid, glutamic acid, glycine, and proline. , Serine and glutamine are contained as freeze-dried products. Isoleucine, leucine, valine and the like are classified as branched-chain amino acids, and in the present invention, the total amount in the infusion composition upon administration is 6 to 61 g / l, preferably 18 to 46 g / l. And more preferably in an amount of 22 to 32 g / l. Lysine, methionine, phenylalanine, threonine, tryptophan, and the like are classified as essential amino acids, and in the present invention, a total of 5 to 70 g is used in the infusion composition at the time of administration.
/ l, preferably 15-47 g / l, more preferably 21
3434 g / l. Histidine, cysteine, tyrosine and the like are classified as pediatric essential amino acids, and in the present invention, in the whole in the infusion composition at the time of administration
The amount is 1.1 to 30 g / l, preferably 2.3 to 17 g / l, more preferably 2.3 to 10 g / l.

In the present invention, the glutamine to be dissolved at the time of use includes solid glutamine, spray-dried glutamine, granular glutamine, lyophilized glutamine, and the like, and lyophilized glutamine is particularly preferred. . Similarly, examples of each amino acid other than glutamine to be dissolved at the time of use include solid, spray-dried, granular, and lyophilized amino acids. Is particularly preferred. When amino acids having poor solubility in water are used as such freeze-dried amino acids, excellent solubility properties and the like can be obtained. Furthermore, the results of our investigation show that cysteine, together with glutamine,
When an amino acid selected from the group consisting of tryptophan, tyrosine, glutamic acid and aspartic acid is lyophilized to a fine powder state, its dissolution rate is extremely good as compared to other amino acids. It was confirmed that the storage stability was also excellent. Further, when an amino acid selected from the group consisting of cysteine and tryptophan, which is relatively poor in stability, is freeze-dried together with glutamine to form a fine powder, the obtained product is excellent in storage stability, and It can be seen that it shows an excellent dissolution rate. In a more preferred embodiment, when cysteine, tryptophan, tyrosine, glutamic acid and aspartic acid are freeze-dried together with glutamine into a fine powder, the storage stability thereof is excellent, and the dissolution rate is excellent. You can recognize that you are. In another preferred embodiment, a branched chain amino acid, such as isoleucine, leucine, valine, and / or an essential amino acid, such as lysine, methionine, phenylalanine, threonine, tryptophan, and / or glutamine.
Or a composition that can be lyophilized into a fine powder to dissolve the essential amino acids such as histidine, cysteine, and tyrosine, and optionally other amino acids such as alanine, arginine, aspartic acid, glutamic acid, glycine, proline, and serine. Which have excellent storage stability and show an excellent dissolution rate. Furthermore, glutamine has excellent solubility in water
(Easily soluble) A solid substance obtained by freeze-drying in the co-presence of an amino acid, preferably in the form of a fine powder, exhibits excellent solubility characteristics in water, and is excellent as a component of the present invention. Is expected. In such a freeze-drying treatment, all or a part of the amino acid to be blended can be present during the freeze-drying treatment of glutamine. Examples of the water-soluble amino acids include lysine, cysteine, proline, serine, glycine, alanine, and arginine.

Thus, the lyophilized glutamine and other amino acids are stored in another container, and are administered at the time of administration (when used).
If it is dissolved in water or an aqueous solution such as a nutrient solution containing an electrolyte, sugars, vitamins, and possibly amino acids,
It has been found that glutamine and other amino acids are rapidly dissolved to form a good glutamine-containing amino acid nutrient solution. When dissolving solid amino acids, such as solid glutamine, it takes a long time to prepare, and there is a risk that intravenous administration may be performed before complete dissolution, and if such There is also a problem that it will lead to an accident if it happens. Therefore, the use of a lyophilized amino acid has the advantage that the danger can be prevented beforehand since the dissolution rate is extremely high. In particular, when a specific amino acid is freeze-dried together with glutamine to form a fine powder, not only is its dissolution rate extremely excellent, but also it has a great advantage in its storage stability. What is completely new is unknown. The amino acid used in the present invention includes not only a commonly used free amino acid but also an organic acid salt, an inorganic acid salt, a metal salt, and any form of di- or tripeptide.

On the other hand, in the present invention, the aqueous solution for dissolving amino acids such as glutamine is a so-called infusion which is generally administered intravenously as hydration, energy or nutritional supplementation. Examples include an electrolyte solution and an amino acid infusion. These infusions and the like include sodium, potassium, magnesium, calcium, chlor, phosphoric acid and other main electrolytes existing inside and outside the cell; glucose, fructose, galactose, xylose,
An infusion solution containing an energy source such as maltose, sorbitol, and xylitol is preferably used for replenishment and maintenance of water and electrolytes, amino acid replenishment, and energy replenishment when oral intake is not possible or insufficient. The aqueous solution for dissolution further includes amino acids such as arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, valine, and proline, as well as monosaccharides and various oligosaccharides and polysaccharides. In some cases, for example, vitamins such as biotin, riboflavin, pyridoxine hydrochloride, folic acid and the like may be blended.

In the present invention, the container for storing the aqueous solution containing the electrolyte, the saccharide and, in some cases, the amino acid, etc., is a single bag type in which the components such as the electrolyte and the saccharide are stored in one container. Alternatively, a double-bag type or a multi-bag type in which components such as an electrolyte and a saccharide are individually stored and mixed at the time of use may be used. In the present invention in this case, in addition to these aqueous solutions such as infusions, in order to increase the calorie replenishment, in order to replenish fat, a container for separately storing a fat emulsion is communicated as a multi-bag type. It is also possible. In short, amino acids such as glutamine (preferably, amino acids such as glutamine, cysteine, tryptophan, tyrosine, glutamic acid, and aspartic acid) are stored separately from these aqueous solutions, and contain water, electrolytes, saccharides, etc. at the time of administration (when used). As long as it can be aseptically communicated so as to be dissolved in an aqueous solution such as a nutrient solution, it goes without saying that such various modifications are also included in the subject of the present invention. For example, when trying to contain a large amount of saccharides in a single bag type, the pH of the solution must be lowered for stability, and undesired side effects such as vascular pain and phlebitis occur clinically, Such a defect can be prevented by the modification of the separate type. That is, the glutamine-containing nutrient solution of the present invention is used for purposes such as enteral tube nutrition as an enteral nutrient solution, central parenteral nutrition as a high-calorie nutrient solution, and peripheral parenteral nutrition as a medium-calorie nutrient solution. For example, it is possible to mix various components in accordance with the above-mentioned means and to store them together or in separate containers. In the present invention, as the fat emulsion, in addition to those which are usually known or used as an infusion, soybean oil, perilla oil, fats such as safflower oil, etc. No.

In the present invention, the glutamine to be dissolved in an aqueous solution such as a so-called infusion solution before use is preferably lyophilized glutamine as described above. Such freeze-dried glutamine has remarkably improved solubility and is instantaneously dissolved in an aqueous solution as compared with other solid glutamines, thereby ensuring safety in use. In addition, in addition to lyophilized glutamine, other unstable amino acids, such as cysteine, tryptophan, etc., or poorly soluble amino acids, such as tyrosine, glutamic acid, aspartic acid, etc., alone or some of them Have been found to provide more favorable solubility properties and storage stability of the preparation. in this case,
Amino acids co-mixed with glutamine are also preferably freeze-dried. Among them, it is preferable to contain cysteine freeze-dried together with glutamine and tryptophan, and it is particularly preferable to contain cysteine, tryptophan, tyrosine, glutamic acid and aspartic acid freeze-dried together with glutamine. is there.

Thus, it is possible to adjust the amino acid balance which could not be achieved by the conventional amino acid infusion, and to simultaneously combine other amino acids with glutamine which is useful as a more effective nutritional infusion. In the amount of the infusion composition of the present invention, the ratio of the amount of each amino acid is as follows: isoleucine 2-16 g / l, leucine 2-20 g / l, valine 4-25 g / l, lysine 1-25 g / l l, methionine 1-8 g / l, phenylalanine 1-11 g / l, threonine 1-18 g / l, tryptophan 1-8 g / l, histidine 1-10 g / l, cysteine 0-10 g / l, Tyrosine 0.1-10 g / l, Alanine 0-50 g / l, Arginine 1-25 g / l, Aspartic acid 0-6 g / l, Glutamic acid 0-10 g / l, Glycine 0-25 g / l, Proline It is possible to prepare an amino acid composition of 0-25 g / l, serine 0-15 g / l and glutamine 10-60 g / l, or an infusion set. Wear. A high glutamine content is achieved in the amino acid composition (glutamine can be stored and transported in a stable state, but can provide a safe infusion), and isoleucine, It is also characterized by the content of branched-chain amino acids such as leucine and valine. The infusion solution also has a characteristic E / N ratio, and for example, one having an E / N ratio close to 1.0 is preferable. The contents of glutamic acid and alanine are also characteristic. At the same time, a high arginine content is achieved. Furthermore, in addition to solid amino acids such as freeze-dried glutamine, saccharides such as glucose, fructose, xylitol, maltose, and sorbitol are added to the container containing the composition (formulation) containing solid amino acids such as glutamine. It is also possible to keep. Furthermore, components other than amino acids that do not affect solid amino acids such as glutamine, for example, electrolyte components such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride; thiamine hydrochloride, sodium riboflavin phosphate, pyridoxine hydrochloride, and ascorbin It is also possible to simultaneously contain vitamins such as acids.

On the other hand, as a counterpart water or an aqueous solution containing electrolytes, saccharides and the like for dissolving a composition (compound) containing a solid amino acid such as glutamine, as described above, water supply, energy supply or nutrition It is a so-called infusion used for intravenous administration as a supplement. Therefore, more specifically, distilled water for injection, electrolyte solution for infusion, amino acid infusion and the like can be mentioned, and these infusions can be used in combination with infusions already commercially available and used clinically. Even in this commercially available infusion, various electrolytes, saccharides, and in some cases, amino acids, fat emulsions, vitamins, fiber components, trace elements, and the like can be selected and combined according to the disease state and nutritional state of the patient to be administered. Needless to say. Further, a stabilizer, a pH adjuster and the like can be appropriately compounded as required. The nutrient solution containing a predetermined amount of glutamine-rich amino acid-containing nutrient solution after lyophilized glutamine and other amino acids of the present invention are dissolved is often administered by intravenous drip. The pH is 4 to 8, preferably 5.5 to 7.5, and the osmotic pressure ratio is not particularly limited, but is preferably 7 or less. When administered from a peripheral vein, the osmotic pressure ratio is preferably 3 or less. .

As described above, the glutamine-containing nutrient solution of the present invention comprises a container containing water or an aqueous solution containing electrolytes, saccharides, and in some cases, an amino acid, and a container containing glutamine and other solid amino acids aseptically. It is manufactured by dissolving a solid amino acid such as glutamine in water or an aqueous solution containing an electrolyte, a saccharide, and optionally an amino acid, etc. Thus, as each storage container applicable to the production of the glutamine-containing nutrient solution, and as a means for connecting both containers, powders to lyophilized pharmaceuticals which have been conventionally proposed and used are dissolved in a dissolution solution at the time of use, and administered by infusion. Alternatively, a kit configured for intravenous administration can be used as it is. As such a kit, for example, a ceftizoxime sodium (eposerine) kit or a cefazolin sodium (cephamedin) kit, which is used for actual clinical treatment as an infusion cephalosporin kit, or various proposals have been made by patent applications. Kit, for example, JP-A-63-13955, JP-A-4-24-2
The infusion container kit disclosed in Japanese Patent Application No. 82159, Japanese Patent Application Laid-Open No. 5-56998, Japanese Patent Publication No. 5-72830, etc. can be used as it is.

Specifically, for example, the lyophilized glutamine of the present invention or the like is stored in a drug storage container in these kits, and water or an electrolyte, a saccharide, and optionally an amino acid are stored in a flexible container for storing a solution. And the like, more specifically, distilled water for injection, electrolyte solution for infusion,
An amino acid infusion solution is stored, and both containers can be mixed and dissolved by aseptic communication with a double-ended needle. In addition, as a communication means of both containers, it is preferable to use a double-ended needle,
The invention is not limited to this, and it is possible to employ cutting or breaking of one of the containers with a needle or a blade, communication with a valve, or the like. In the present invention, both the solid component and / or the liquid component constituting the infusion preparation set can be aseptically produced according to a known method. Each of the components can be manufactured, sterilized, and / or stored under an atmosphere of an inert gas such as nitrogen gas or helium gas. Further, for the sterilization, a suitable method is selected as necessary, for example, high-pressure steam sterilization, gas sterilization, irradiation (for example, radiation such as ultraviolet rays, electromagnetic waves, and γ-rays, and high frequency), and filtration sterilization (sterile filtration). But can be done,
For components that are unstable to heat or the like, sterilization by filtration is preferred. The components can be individually sterilized, or can be treated by different sterilization methods. Next, the freeze-drying treatment in the present invention can similarly be performed aseptically in accordance with a known method, and is usually a freeze-dryer used in the art (for example, in a stainless steel drying oven). It can be carried out using a shelf on which containers such as filled vials and ampoules are placed, a condenser (cold trap), a refrigerator, a heating device, a vacuum device, and a control device therefor. In the present invention, glutamine and other amino acids can be lyophilized either alone or in the presence of each other, and are appropriately selected according to the purpose and the like. In addition, each amino acid is another substance (preferably a water-soluble compound such as, for example,
Lyophilization can be performed in the presence of sugars such as glucose, inorganic salts such as sodium chloride) and / or in the presence of a buffer, a pH adjuster and a solubilizer. It is appropriately selected according to the purpose and the like.

The infusion solution containing the amino acid of the above composition of the present invention can be used in a pathological condition such as a surgical invasion after burns, trauma, surgery, etc., or an acute infectious disease caused by microbial infections such as bacteria and viruses. When used, significant effects can be expected. Further, the infusion suppresses muscle protein breakdown, promotes protein synthesis, promotes nucleic acid synthesis in immune cells, activates immune cells, enhances bactericidal action of neutrophils, suppresses intestinal mucosal atrophy, and maintains intestinal mucosal structure , Suppression of intestinal mucosal permeability increase, promotion of sodium and water absorption, improvement of nutrient absorption, promotion of liver regeneration, suppression of fatty liver, promotion of glutathione production, suppression of in vivo peroxidation, improvement of nitrogen balance, It can be used for the purpose of obtaining an administration effect selected from the group consisting of promotion of wound healing, suppression of pancreatic atrophy, and promotion of renal arginine production. In addition, the infusion may be used for burn, trauma, surgery, acute infection, chronic infection, severe catabolism such as bone marrow transplantation, progressive malignant disease, intestinal dysfunction (inflammatory bowel disease, infectious enteritis, short bowel syndrome, And post-radiation therapy) and immunodeficiency syndrome. Such actions and effects can be confirmed by appropriate means. The infusion solution of the present invention containing an amino acid having the above composition contains an appropriate amount of the amino acid, and therefore has excellent amino acid replenishing properties, and can be preferably and conveniently used for the above-mentioned uses and purposes. The infusion containing the amino acid of the above composition of the present invention can be preferably administered by infusion or intravenous administration for the above-mentioned uses and purposes.

[0029]

EXAMPLES The present invention will be described in more detail with reference to the following examples. However, the present invention is not limited to these examples, and various embodiments are possible. It is to be understood that all embodiments are included as long as they are in line with the spirit. Preparation Example 1 : The following preparation experiment was performed using a kit in which a vial having a capacity of 300 mL was connected to one side of a polyethylene bag having a capacity of 1500 mL via a double-ended needle. (1) As amino acid infusion, "L-Ile; 56.00 g, L-Leu; 1
25.00 g, L-Val; 45.00 g, L-Lys acetate; 124.00 g, L-Me
t; 35.00g, L-Phe; 93.50g, L-Thr; 65.00g, L-Trp;
13.00 g, L-His; 60.00 g, L-CysSH; 10.00 g, L-Tyr;
3.50 g, L-Ala; 62.00 g, L-Arg; 79.00 g, L-Asp; 38.00 g
, L-Glu; 65.00g, Gly; 107.00g, L-Pro; 33.00g, L
-Ser; 22.00 g, L-Gln; 300.00 g, Na bisulfite; 1.500
g ”was weighed, dissolved in distilled water for injection, made up to 10 L, sterilized by filtration through a 0.22 μm membrane filter, filled into vials of 200 mL each, and freeze-dried. (2) Separately, sugar and electrolyte "glucose; 1200.0g
, Sodium chloride; 29.200 g, potassium acetate; 21.600 g
, Potassium dihydrogen phosphate; 10.880 g, sulfuric acid Mg-7H ₂ O;
7.400g, ₂ gluconate Ca-H O; 17.920g, sulfate Zn · 7H ₂ O;
57.52 mg ", dissolve in distilled water for injection, adjust the pH to 4.5 with citric acid, make up to 10 L, filter, and filter.
L was filled into a polyethylene plastic bag, plugged and welded, and then subjected to heat steam sterilization. The vial (1) and the plastic bag (2) were combined via a double-ended needle to obtain a glutamine-containing amino acid infusion preparation. As a result of mixing the obtained glutamine-containing amino acid infusion preparation by a predetermined operation, the time required for dissolution is as follows:
The total time for 10 bags was 7 minutes. It dissolved in a short time and showed good solubility properties. This glutamine-containing amino acid infusion preparation was stable, with no glutamine degradation observed even for 24 hours. The total free amino acid in 1 L of the obtained glutamine-containing infusion preparation was 26.00 g, and the total nitrogen amount was
4.19g, E / N ratio is 0.67.

Preparation Example 2 The following preparation experiment was performed using a polyethylene double bag having a 1200 mL capacity chamber and a 500 mL capacity chamber, in which the center of a polyethylene bag was separated into two chambers so as to be peelable by a fragile seal. went. (1) Glucose as a sugar / electrolyte infusion preparation; 749.980
g, sodium chloride; 7.980 g, sodium lactate (50%
Liquid); 45.780 g, Ca ・ H ₂ O gluconate: 11.200 g, Mg sulfate
・ 7H ₂ O; 6.230 g, Zn ・ 7H ₂ O; 14.00 mg, bisulfite
Na; 0.30 g "was weighed, dissolved in distilled water for injection, and then pH
Was adjusted to 5.0, and the volume was increased to 10 L.
One room (capacity: 1200 mL) of E double bag was filled to 1 L, plugged and welded, and then heated and steam sterilized. (2) Separately, "L-Ile; 119.25
g, L-Leu; 155.25 g, L-Val; 91.50 g, L-Lys acetate; 17
7.75 g, L-Met; 55.50 g, L-Phe; 89.25 g, L-Thr; 72.
00g, L-Trp; 26.25g, L-His; 39.75g, L-CysSH; 7.5
0 g, L-Tyr; 3.75 g, L-Ala; 48.75 g, L-Arg; 112.50 g,
L-Asp; 7.50 g, L-Glu; 3.00 g, Gly; 24.75 g, L-Pro; 4
1.25 g, L-Ser; 26.25 g, L-Gln; 450.00 g, bisulfite
Na; 2.250 g, dipotassium phosphate; 58.00 g "were weighed, dissolved in distilled water for injection, and made up to 10 L. This aqueous solution is sterilized by filtration through a 0.22 μm membrane filter under aseptic conditions, and the lyophilized product is transferred in a lump to a container that can be transferred.
Each 300 mL was filled and freeze-dried, and the whole amount of the freeze-dried product was filled into another chamber of a double bag made of PE having a capacity of 500 mL and welded to obtain a glutamine-containing amino acid infusion preparation. The obtained glutamine-containing amino acid infusion preparation was communicated and mixed by a predetermined operation, and as a result, the time required for dissolution was 5 minutes in total of 10 bags. It dissolved in a short time and showed good solubility properties. This glutamine-containing amino acid infusion preparation was stable, with no glutamine degradation observed even after 24 hours.
It contains 30.0 g of total free amino acid and 4.91 g of total nitrogen in 1 L of this glutamine-containing amino acid infusion preparation, and has an E / N ratio of 0.96.

Preparation Example 3 A polyethylene bag having a capacity of 400 mL was placed in one of a polyethylene double bag having two chambers each having a capacity of 1000 mL and a capacity of 500 mL in which the center of a polyethylene bag was detachably separated by a fragile seal into two chambers. The following preparation experiment was carried out using a kit in which the vials were connected via a double-ended needle. (1) As glucose and electrolyte for infusion, "glucose; 781.250g,
Sodium chloride; 10.963 g, potassium chloride; 4.663 g, calcium chloride ・ 2H ₂ O; 2.300 g, Mg chloride ・ 6H ₂ O; 1.913 g,
Potassium glycerophosphate (50% solution); 31.0375 g, sodium L-lactate (50% solution); 28.025 g, citric acid; 0.176 g "
Was weighed, dissolved in distilled water for injection, adjusted to pH 6.0 with L-lactic acid, and the total amount was adjusted to 10 L. After filtration, one chamber (capacity: 1000 mL) of the PE double bag was filled to a volume of 800 mL, and clogged and welded. (2) As a fat infusion, weigh 1000.0 g of refined soybean oil,
120.0 g of purified egg yolk lecithin and 220.0 g of concentrated glycerin were added to distilled water for injection to make 3 L, and stirred with a homomixer,
A crude emulsion was prepared. Thereafter, the mixture was emulsified by a high-pressure emulsification method, and distilled water for injection was added to make a total volume of 10 L. After filtration, P
Another room (capacity: 500 mL) of the double bag made of E was filled to a volume of 200 mL, closed and welded, and then the double bag was sterilized. (3) Separately, L-Ile; 79.
50 g, L-Leu; 103.50 g, L-Val; 61.00 g, L-Lys acetate;
118.50 g, L-Met; 37.00 g, L-Phe; 59.50 g, L-Thr; 4
8.00 g, L-Trp; 17.50 g, L-His; 26.50 g, L-CysSH;
5.00 g, L-Tyr; 2.50 g, L-Ala; 32.50 g, L-Arg; 75.00 g
, L-Asp; 5.00 g, L-Glu; 2.00 g, Gly; 16.50 g, L-Pr
o; 27.50 g, L-Ser; 17.50 g, L-Gln; 300.00 g, Na bisulfite; 1.500 g '' were weighed and dissolved in distilled water for injection to 10
L was raised to L. The aqueous solution was filtered through a 0.22 μm membrane filter, filled into vials of 300 mL each, and freeze-dried. The PE plastic bags of (1) and (2) and the vial of (3) were combined via a double-ended needle to obtain a glutamine-containing fat-added amino acid infusion preparation. The resulting glutamine-containing fatty acid-added amino acid infusion preparation was communicated and mixed by a predetermined operation, and as a result, the time required for dissolving glutamine was 10 minutes in a total of 10 bags. It dissolved in a short time and showed good solubility properties. This glutamine-containing fatty acid-added amino acid infusion preparation was stable, with no glutamine degradation observed even after 24 hours. The total free amino acids in 1 liter of the glutamine-containing fat-added amino acid infusion preparation were 30.00 g, the total nitrogen amount was 4.91 g, and the E / N ratio was 0.96.
It is.

[0032]

The present invention provides an infusion solution which contains glutamine stably and can be used at a higher content, and which can replenish each amino acid in a well-balanced manner. The amino acid-containing infusion prepared using the infusion set provided by the present invention can be expected to be administered to living bodies in various states to obtain excellent amino acid replenishment performance. Also, if the infusion set provided by the present invention is used,
It is possible to obtain an infusion solution that can be rapidly and safely administered.

Claims (8)

[Claims] (1) isoleucine 2 to 16 g / l, leucine 2 to
20 g / l, valine 4-25 g / l, lysine 1-25 g / l, methionine 1-8 g / l, phenylalanine 1-11 g / l, threonine 1-18 g / l, tryptophan 1-8 g / l, histidine 1-10 g / l, cysteine 0-10 g / l, tyrosine 0.1-
10 g / l, alanine 0-50 g / l, arginine 1-25 g / l,
Aspartic acid 0-6 g / l, Glutamic acid 0-10 g /
l, glycine 0-25 g / l, proline 0-25 g / l, serine
A solid amino acid composition containing each amino acid in an amount to give 0-15 g / l and glutamine 10-60 g / l in an infusion composition at the time of administration. 2. Leucine 8 to isoleucine 5 to 10 g / l, leucine 8 to
16 g / l, valine 5-20 g / l, lysine 5-15 g / l, methionine 3-6 g / l, phenylalanine 3-10 g / l, threonine 3-10 g / l, tryptophan 1-6 g / l, histidine
2-9 g / l, cysteine 0.1-5 g / l, tyrosine 0.2-3
g / l, alanine 0.1-10 g / l, arginine 5-15 g / l,
Aspartic acid 0.4-4 g / l, Glutamic acid 0.1-6 g /
l, glycine 0.1-14 g / l, proline 1-10 g / l, serine
2. The solid amino acid composition according to claim 1, wherein each amino acid is contained in an amount of 1 to 10 g / l and glutamine 15 to 50 g / l in the infusion composition at the time of administration. 3. Leucine 10 isoleucine 6-8 g / l, leucine 10
-14 g / l, valine 6 -10 g / l, lysine 8-11 g / l, methionine 3-5 g / l, phenylalanine 5-8 g / l, threonine 4-8 g / l, tryptophan 1-2 g / l, histidine 2-7 g / l, cysteine 0.1-2 g / l, tyrosine 0.2
~ 1 g / l, alanine 0.2 ~ 5 g / l, arginine 7 ~ 13 g /
l, aspartic acid 0.5-2 g / l, glutamic acid 0.2-2
g / l, glycine 1-13 g / l, proline 2-7 g / l, serine 1.5-7 g / l and glutamine 15-40 g / l in the amount given in the infusion composition at the time of administration, each amino acid The solid amino acid composition according to claim 1, comprising: 4. Glutamine is a freeze-dried product, or an amino acid selected from the group consisting of cysteine, tryptophan, tyrosine, glutamic acid and aspartic acid, and glutamine are lyophilized products. 3. The solid amino acid composition according to any one of 3. 5. The solid according to claim 1, wherein the freeze-dried glutamine is obtained by freeze-drying together with glutamine and another substance in a weight ratio to glutamine of 0.8 or more. Amino acid composition. 6. A composition comprising the solid amino acid composition according to any one of claims 1 to 5 and an aqueous solution containing water or a substance selected from the group consisting of electrolytes, saccharides, amino acids, and the like. A combination infusion preparation characterized in that the combination is one set. 7. The weight ratio of (a) glutamine to (b) one selected from the group consisting of amino acids other than glutamine, saccharides, electrolytes and vitamins is 0.8 or more. The infusion preparation according to the above. 8. The solid amino acid composition according to claim 1, wherein the solid amino acid composition is dissolved in water or an aqueous solution containing one selected from the group consisting of electrolytes, saccharides, amino acids and the like. For producing amino acid-containing preparations.