JPH09294565A - Nutriotious solution containing glutamic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently obtain the subject nutritious solution useful for transfusion, etc., by aseptically connecting a container containing water or an aqueous solution containing an electrolyte, a saccharide, an amino acid, etc., to a container containing glutamine, making both the containers communicate with each other in use and dissolving the glutamine. SOLUTION: This nutritious solution containing glutamine is obtained by aseptically connecting a container containing water or an aqueous solution containing an electrolyte such as sodium, potassium, magnesium, chloride or phosphoric acid, a saccharide such as glucose or xylitol or an amino acid such as arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine or proline present on the inside or outside of a cell to a container containing glutamine, cysteine and/or tryptophan, simultaneously making both containers communicate with each other through a double ended needle, etc., thereby dissolving the glutamine in the water or the aqueous solution containing the electrolyte, saccharide, amino acid, etc. The resultant nutritious solution is useful for transfusion, etc., in nutritional control, etc., when the meal cannot perorally be ingested.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a glutamine-containing nutrient solution and a method for producing the same, and more specifically, a glutamine-containing nutrient solution in which glutamine is dissolved in water or a nutrient solution containing an electrolyte, sugar, amino acid, etc. at the time of use. And its manufacturing method.

[0002]

2. Description of the Related Art It has become possible to easily perform nutritional management by a complete parenteral nutrition method in patients who cannot or cannot ingest a nutritional source such as food due to digestive system diseases or other causes. That is, the intravenous amino acid nutritional infusion can be orally ingested for nutritional supplementation during various diseases, or before or after surgery, although it is necessary to take in amino acids, proteins, etc.
Alternatively, it is widely used for nutritional management when the intake is insufficient. Furthermore, in recent years, studies on the amino acid composition in nutritional infusion have been actively conducted, and unlike other amino acids, branched chain amino acids (BCAA: Branched-chain Amino Acid) which are mainly metabolized in tissues other than the liver.
Amino acid preparations for catabolism based on the nutritional significance of ds) and amino acid preparations for various diseases have been developed, and infusions for the purpose of not only nutritional supplementation but also alleviation and treatment of medical conditions should be used. Is becoming.

By the way, these amino acid nutritional infusion solutions that have been commercially available so far contain various essential amino acids, but do not contain glutamine. This is a non-essential amino acid in which glutamine is abundant in the body and can be synthesized from other amino acids without ingestion from outside the body. Furthermore, when glutamine is formulated, it has poor solubility and poor chemical stability. Was one of the causes. However, in recent studies, large amounts of glutamine are synthesized and released from skeletal smooth muscles during surgical invasion and during severe infections, and become a cellular energy substrate for the intestinal mucosa and immune system. The importance of metabolism has been clarified, and it has become clear that it is necessary to supply sufficient glutamine from outside the body. However, as described above, glutamine has low solubility in various aqueous solutions, and further, chemical instability in a solution state makes it impossible to prepare an amino acid nutrition infusion solution containing glutamine itself. Therefore, as a pharmaceutical device for administering a sufficient amount of glutamine in a stable form, glycyl-
Glutamine (Gly-Gln), Alanyl-Glutamine (Ala-Gl)
n), a means for administering a necessary amount of glutamine as a dipeptide derivative such as arginyl-glutamine (Arg-Gln) has been proposed.

However, there are the following problems when glutamine is administered as a dipeptide derivative in an amino acid nutritional infusion. That is, since glutamine is most abundant with 30 to 50% of the total amount of free amino acids in the whole body, when incorporated into an infusion preparation containing 10% normal amino acids, glutamine is about 3% (that is, 30% of the total amount of amino acids). Degree) will have to be blended. In this case, if glutamine is contained as a dipeptide derivative, the amino acid of the other partner that is paired with glutamine will inevitably be mixed in an equimolar amount, resulting in overdose of the amino acid and an imbalance of the entire amino acid. To do. In addition, addition of glutamine as a dipeptide derivative and addition of other required amino acids is not preferable from the viewpoint of total nitrogen content in the infusion solution, and it is also included in that respect. An amino acid imbalance occurs. Therefore, under the present circumstances where the importance of the glutamine feeding method is recognized, it is strongly desired to develop a nutrient solution containing glutamine in a well-balanced amino acid nutrient solution.

[0005]

The present invention has been completed in view of the above points, and among the conventionally proposed glutamine-free amino acid nutrient transfusions, electrolytes, and the like,
It is an object to propose a glutamine-containing nutrient solution that can be administered by dissolving a sufficient amount of glutamine in a stable form at the time of use.

[0006]

Means for Solving the Problems As a means therefor, the present invention is an aseptic connection between a container for storing water or an aqueous solution containing an electrolyte, sugar, amino acid, etc. and a container for storing glutamine. Provided is a method for producing a glutamine-containing nutrient solution, which is characterized in that glutamine is allowed to communicate with each other at the time of use, thereby dissolving glutamine in water or an aqueous solution containing an electrolyte, sugar, amino acid and the like.

In the present invention, examples of glutamine to be dissolved at the time of use include solid glutamine, spray-dried glutamine, granular glutamine, and freeze-dried glutamine. Of these, freeze-dried glutamine is particularly preferable. It has been found. That is, as a result of the examination by the present inventors, when glutamine is freeze-dried into a fine powder state, its dissolution rate is extremely good as compared with other solid glutamine, and in a freeze-dried product. However, it was confirmed that the storage stability was excellent. Therefore, if the freeze-dried glutamine is stored in another container and dissolved in water or an aqueous solution such as a nutrient solution containing an electrolyte, sugar, amino acid, etc. at the time of administration (at the time of use), glutamine will be rapidly dissolved, which is good. It has been newly found that it becomes a nutrient solution containing various glutamines.
When dissolving solid glutamine, it takes a long time to prepare it, and there is a risk of causing an accident if intravenous administration is performed before it is completely dissolved. Therefore, the use of freeze-dried glutamine has an advantage that it can prevent such a risk because the dissolution rate is extremely fast, and such means is a novel novel method that has not been known so far. Therefore, as a more preferred embodiment of the present invention, a container for storing water or an aqueous solution containing an electrolyte, sugar, amino acid, etc. and a container for storing freeze-dried glutamine are aseptically connected, and both containers are in use. Glutamine lyophilized by communication with water or electrolyte,
A method for producing a glutamine-containing nutrient solution, which comprises dissolving it in an aqueous solution containing sugar, amino acid and the like.

On the other hand, in the present invention, the aqueous solution in which glutamine is dissolved is a so-called infusion solution which is generally administered intravenously for hydration, energy supplementation or nutrition supplementation, such as water, distilled water for injection, and electrolyte solution for infusion. Examples include amino acid infusions. These infusions include sodium, potassium, magnesium, chloro, phosphate, and other main electrolytes existing inside and outside the cell; glucose, xylitol, and other energy sources; and arginine, histidine,
Contains amino acids such as isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, proline, etc., and replenishes / maintains water / electrolyte when ingestion is impossible or insufficient,
Infusion solutions used for amino acid supplementation and energy supplementation are preferable.

Therefore, as a more preferred embodiment of the present invention, a container for storing water or an aqueous solution such as distilled water for injection and a container for storing glutamine are aseptically connected, and both containers are connected at the time of use. And a method for producing a glutamine-containing nutrient solution, which comprises dissolving lyophilized glutamine in water such as distilled water for injection.

In still another more preferred embodiment, the present invention is an aseptic connection between a container for storing water or an aqueous solution containing an electrolyte, sugar, amino acid, etc. and a container for storing freeze-dried glutamine. Disclosed is a method for producing a glutamine-containing nutrient solution, characterized in that the container is communicated at the time of use, and thereby the freeze-dried glutamine is dissolved in an aqueous solution containing an electrolyte, sugar, amino acid and the like.

In the present invention, the container for storing the aqueous solution containing the electrolyte, sugar, amino acid and the like is a single bag type container in which the components such as electrolyte, sugar and amino acid are stored in one container. Further, it may be a double bag type or a multi bag type in which components such as an electrolyte, sugar and amino acid are separately stored and mixed at the time of use. In the present invention in this case, in addition to these aqueous solutions such as infusion solutions, in order to enhance the calorie supplementation, a container for separately storing the fat emulsion is connected as a multi-bag type in order to supplement the fat content. It is also possible. In short, glutamine may be stored separately from these aqueous solutions, and may be aseptically communicated at the time of administration (at the time of use) so as to be dissolved in water or an aqueous solution of a nutrient solution containing an electrolyte, sugar, amino acid, etc., It goes without saying that such various modifications are also included in the subject matter of the present invention. For example, when trying to contain a large amount of sugars in the single bag type, the pH of the solution must be lowered for stability, and clinical vascular pain,
Although undesired side effects such as phlebitis occur, 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 its purpose, for example, enteral tube feeding as a enteral component nutrient solution, central parenteral nutrition as a high-calorie nutrient solution, and peripheral parenteral nutrition as a medium-calorie nutrient solution. It is possible to modify by mixing various components according to the means such as the above and storing them together or in separate containers.

Further, the present invention provides a glutamine-containing nutrient solution itself in which glutamine is efficiently dissolved, and specifically provides a nutrient solution produced by using the above-mentioned production method. Considering that there has been no glutamine-containing nutrient solution in which glutamine has been efficiently dissolved in an infusion solution, it can be said that the nutritional solution provided by the present invention is extremely useful in medicine.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the glutamine dissolved in an aqueous solution such as a so-called infusion solution at the time of use is preferably lyophilized glutamine as described above. The freeze-dried glutamine has significantly improved solubility and is instantly dissolved in an aqueous solution as compared with other solid glutamines, so that safety in use is ensured. So, for example, 1
Even when glutamine is added to a 0% amino acid infusion, the amount of 3 to 4% (30 to 4% of the total amino acid amount)
It has become possible to incorporate glutamine as 0%). In the container for storing the freeze-dried glutamine according to the present invention, it is generally 0.5 although it varies depending on the amino acid content in the aqueous solution of the other party in which glutamine is dissolved.
The amount may be from about 50 to 50 g, preferably from 2 to 20 g, more preferably from 6 to 12 g.

In the container for storing glutamine,
In addition to freeze-dried glutamine, other unstable amino acids, such as cysteine and tryptophan, or low-solubility amino acids, such as tyrosine, glutamic acid, and aspartic acid, either alone or in combination at the same time. It is also possible to keep it. In this case, it is preferable that the amino acid simultaneously mixed with glutamine is also a freeze-dried product. Above all, it is preferable to contain lyophilized cysteine and tryptophan together with glutamine. By selecting other amino acids simultaneously mixed with this glutamine according to the patient to be administered, it is possible to prepare an amino acid balance that could not be achieved by conventional amino acid infusion, and prepare a more effective nutrition infusion. can do.
Further, in the container for storing glutamine, in addition to freeze-dried glutamine, sugars such as glucose, fructose, xylitol, maltose and sorbitol can be blended. Furthermore, components other than amino acids that do not affect glutamine, such as electrolyte components such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride; vitamins such as thiamine hydrochloride, sodium riboflavin phosphate, pyridoxine hydrochloride, and ascorbic acid. It is also possible to include at the same time.

On the other hand, the water containing the other party in which glutamine is dissolved or an aqueous solution containing an electrolyte, sugar, amino acid, etc. is conventionally used for intravenous administration as hydration, energy supplement or nutrition supplement as described above. It is an infusion. 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 clinically commercially available and used infusions. Even in this commercially available infusion, etc., various electrolytes, sugars, amino acids, fat emulsions,
It goes without saying that vitamins, fiber components, trace elements, etc. can be selected and mixed. The glutamine-containing nutrient solution after the lyophilized glutamine of the present invention is dissolved is often administered intravenously, and thus the prepared nutrient solution has a pH of 4 to 8, preferably 5 Although the osmotic pressure ratio cannot be unconditionally limited, it is 0.5 to 7.5.
The osmotic pressure ratio is preferably 3 or less when administered from a peripheral vein.

As described above, the glutamine-containing nutrient solution of the present invention is aseptically connected to a container containing water or an aqueous solution containing an electrolyte, sugar, amino acid, etc. and a container containing glutamine. It is produced by allowing glutamine to communicate with each other, thereby dissolving glutamine in water or an aqueous solution containing an electrolyte, sugar, amino acid and the like. However, as a storage container applicable to the production of the glutamine-containing nutrient solution, and as a means for connecting both containers, powder-lyophilized pharmaceuticals that have been proposed and used in the past are dissolved in a solution at the time of use, and drip administration is performed. Alternatively, a kit configured for intravenous administration can be used as it is. As such a kit, for example, ceftizoxime sodium (eposerine) kit or cefazolin sodium (cephamedin) kit which is actually used for clinical treatment as a cephalosporin kit for infusion, or variously proposed by patent application Some kits, for example, JP-A-63-13955 and JP-A-4-282
159, JP-A-5-56998, and JP-B-5
The infusion container kit disclosed in Japanese Patent Publication No. -72830 can be used as it is.

Specifically, for example, the freeze-dried glutamine of the present invention is stored in the drug storage container in these kits, and water or an aqueous solution containing an electrolyte, sugar amino acid, etc. is placed in a flexible container for storing the solution. , More specifically,
Distilled water for injection, electrolyte solution for infusion, amino acid infusion solution can be stored, and both containers can be mixed and dissolved by aseptic communication with a double-ended needle. In addition, as a communication means for both containers,
It is preferable to use a double-ended needle, but not limited to this, and cutting or breaking with a needle or blade of one container,
It is possible to employ communication using a valve.

Thus, the glutamine-containing nutrient solution of the present invention is produced, and a more specific production will be described below. Preparation Example 1 : As the kit, the kit described in JP-B-5-72830 was used. Freeze-dried glutamine 15
g was aseptically filled in a drug vial, and 500 ml of Solitax (registered trademark) -H (manufactured by Shimizu Pharmaceutical Co., Ltd.), which is an electrolyte solution for infusion, was filled in a flexible container as one container. Both containers were aseptically communicated using a double-ended needle to dissolve glutamine in Soritax-H. The freeze-dried glutamine in the vial was instantaneously dissolved in Solitax-H with the communication of both containers by the double-ended needle, and the desired glutamine-containing nutrient solution was prepared. The obtained glutamine-containing nutrient solution was stable with no decomposition of glutamine itself observed even after 24 hours.

Preparation Example 2 : As a kit, Japanese Patent Publication No. 5-7
The kit described in Japanese Patent No. 2830 was modified and used.
That is, a drug vial was aseptically filled with 8 g of freeze-dried glutamine, one container of a flexible container was made into a double bag type, and 500 ml of Solitax-H, which is an electrolyte solution for infusion, was placed in the first bag. The second bag was filled with 120 ml of Aminic (registered trademark) (manufactured by Morishita Roussel), which is a 10% amino acid preparation. The first bag and the second bag were communicated with each other to mix both solutions.
Immediately after that, the glutamine-containing container was connected with a double-ended needle to dissolve glutamine in the mixed solution. The lyophilized glutamine in the vial was instantaneously dissolved in the mixed solution of Solitax-H and Aminic with the communication with a double-ended needle.
The desired glutamine-containing nutrient solution was prepared. The non-protein calorie of the obtained glutamine-containing nutrient solution is 250 Kca
1 and the total amino acid content was 20 g, 40% of which was glutamine and the N content was 3.2.
Therefore, the non-protein calorie / N amount was 78, and this nutrient solution was suitable as a nutrient solution based on the peripheral parenteral nutrition method. The obtained glutamine-containing nutrient solution was also stable, with no decomposition of glutamine itself observed even after 24 hours.

Preparation Example 3 : As a kit, Japanese Patent Publication No. 5-7
The kit described in Japanese Patent No. 2830 was modified and used.
That is, a drug vial was aseptically filled with 8 g of lyophilized glutamine, one flexible container was made into a triple bag type (multi-bag type), and a 20% fat emulsion was used in the first bag. 100 ml of Intrafat (registered trademark) (manufactured by Nippon Pharmaceutical Co., Ltd.) was filled, and Solitax-H, an electrolyte solution for infusion, was filled in the second bag.
The third bag was filled with 750 ml, and the third bag was filled with 150 ml of aminic, which is a 10% amino acid preparation. The first bag, the second bag, and the third bag were communicated with each other, and the respective three liquids were mixed. Immediately after that, the glutamine-containing container was connected with a double-ended needle to dissolve glutamine in the mixed solution. The freeze-dried glutamine in the vial was instantaneously dissolved in the mixed solution of the three liquids with the communication with a double-ended needle to prepare the desired glutamine-containing nutrient solution. The non-protein calorie of the obtained glutamine-containing nutrient solution is 575
Kcal, the total amino acid content was 23 g, 35% of which was glutamine and the N content was 3.68. Therefore, the non-protein calorie / N amount is 156
This nutrient solution was suitable as a nutrient solution based on the peripheral parenteral nutrition method. The obtained glutamine-containing nutrient solution was also stable, even after 24 hours, without degrading glutamine itself.

[0021]

INDUSTRIAL APPLICABILITY As described above, the present invention provides a nutrient solution in which glutamine could not be blended efficiently until now. Under the present circumstances where the importance of the glutamine feeding method is recognized, It can be said that the advantage of providing a nutrient solution containing glutamine in good balance in the amino acid nutrient solution is great.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical display location A61K 33/00 B65D 85/72 F B65D 85/72 A61J 1/00 351A

Claims (9)

[Claims] 1. A container for accommodating water or an aqueous solution containing an electrolyte, sugar, amino acid, etc. and a container for accommodating glutamine are aseptically connected, and both containers are in communication at the time of use, whereby the glutamine is separated from water or A method for producing a glutamine-containing nutrient solution, which comprises dissolving it in an aqueous solution containing an electrolyte, sugar, amino acid and the like. 2. The method for producing a glutamine-containing nutrient solution according to claim 1, wherein the glutamine is freeze-dried glutamine. 3. The container containing glutamine further contains cysteine and / or tryptophan.
Alternatively, the method for producing a glutamine-containing nutrient solution according to item 2. 4. The method for producing a glutamine-containing nutrient solution according to claim 1, wherein the container containing glutamine further contains a saccharide. 5. The container for accommodating water or an aqueous solution containing an electrolyte, sugar, amino acid, etc. is aseptically communicated with a container for accommodating a fat emulsion, and both containers are communicated at the time of use. The method for producing a glutamine-containing nutrient solution according to any one of claims. 6. The method for producing a glutamine-containing nutrient solution according to claim 1, wherein the communicating means is performed via a double-ended needle. 7. A container for storing water or an aqueous solution containing an electrolyte, sugar, amino acid, etc. and a container for storing glutamine are aseptically connected, and both containers are communicated with each other at the time of use, whereby the glutamine is mixed with water or A glutamine-containing nutrient solution characterized by being dissolved in an aqueous solution containing an electrolyte, sugar, amino acid and the like. 8. A container for storing water or an aqueous solution containing an electrolyte, sugar, amino acid, etc. and a container for storing freeze-dried glutamine are aseptically connected, and both containers are communicated at the time of use, thereby freezing. A glutamine-containing nutrient solution characterized in that dried glutamine is dissolved in water or an aqueous solution containing an electrolyte, sugar, amino acid and the like. 9. A storage container containing freeze-dried glutamine, which is in communication with a container for storing water or an aqueous solution containing an electrolyte, sugar, amino acid, etc. so that the freeze-dried glutamine is dissolved at the time of use.