JP2003160501A - Infusion preparation containing a trace of metal - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a infusion preparation in which a trace of metal containing solution, iodine ion solution, amino acid solution, sugar solution and other chemical containing solutions are consolidated in an infusion container in the absence of oxygen and a trace of metal and iodine do not precipitate during storage. <P>SOLUTION: The nutritious infusion preparation is enclosed in a gas barrier outerbag practically in the absence of oxygen and comprised of a plurality of chambers separated by communicable walls which house an amino acid- containing solution in the first chamber, a sugar-containing solution in the second chamber and a trace metal-containing solution in the third chamber. Solutions in the first and/or second chambers of this nutritious infusion preparation contain an iodine ion. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a nutritional infusion preparation having an infusion container having a plurality of chambers capable of preparing and blending medicines, and a method of stabilizing iodine ion or copper ion using the container. It is a thing.

[0002]

2. Description of the Related Art High calorie infusions are intravenously administered to patients who are unable or unable to receive oral and enteral nutrition. As the infusion formulation used at this time,
Sugar preparations, amino acid preparations, electrolyte preparations, mixed vitamin preparations, fat emulsions, etc. are commercially available, and they are appropriately mixed and used in hospitals at the time of use depending on the disease state. However, such a mixed injection operation in a hospital is complicated, and there is a problem that there is a high possibility of bacterial contamination during operation and it is unsanitary. For this reason, an infusion container having a plurality of chambers partitioned by a separable partition means has been developed and widely used in hospitals. As a product of this infusion container, for example, there is one in which an amino acid infusion is contained in one room and a glucose infusion is contained in another room. However, since the amino acid infusion is susceptible to oxidative decomposition by oxygen, the infusion container has a gas barrier Encased in a plastic film bag with oxygen scavenger.

On the other hand, trace metals (copper,
Since iron, zinc, manganese, etc.) are not contained, if the infusion is administered for a long period of time, so-called trace metal deficiency, in which the patient's lips crack or hematopoietic function deteriorates, develops. For this reason, in the current situation, hospitals still properly mix trace metal elements immediately before administering an infusion, despite the problem of bacterial contamination.

In view of the present situation, the present inventors have started to study an infusion preparation containing a trace amount of metal element in one chamber of an infusion container. However, when combining an amino acid infusion solution with a trace metal element, that is, in the absence of oxygen, if the trace metal and the iodine ion are housed in the same chamber, the trace metal and the iodine ion, which were conventionally considered to be stable, are The present inventors have found that they react and produce a precipitate.

That is, it was conventionally recognized that trace metals and iodide ions do not cause precipitation even when mixed in an aqueous medium. For example, an infusion preparation containing an oxygen-sensitive component such as an amino acid preparation. Is contained in a gas permeable container, and the container is covered with an outer bag that does not allow gas to permeate with the oxygen scavenger until just before use so that it is not affected by oxygen as much as possible. The present inventors have found that, in the absence of the above, when trace metals (particularly copper) and iodide ions are housed in the same chamber, precipitation easily occurs and the commercial value of the infusion preparation is lost.

[0006]

SUMMARY OF THE INVENTION According to the present invention, a trace amount metal solution is contained in one chamber of an infusion container and an iodine ion solution, an amino acid solution or the like is contained in another chamber under the condition that oxygen is substantially absent. Therefore, it is an object of the present invention to provide an infusion preparation in which trace metals and iodine ions do not form a precipitate during storage and copper ions and iodine ions are stable.

[0007]

In view of the above problems, the present inventors have adopted an infusion container having a multi-chamber infusion container capable of separately containing a trace amount metal solution and an iodine ion solution, and a plurality of infusion containers are used at the time of use. It was found that the above problems can be solved by mixing various solutions stored in an infusion container by communicating them.

What achieves the above-mentioned object is, for example, an infusion container having a plurality of chambers which are partitioned so that they can communicate with each other at the time of use. Further, the infusion container includes a first chamber, a second chamber partitioned from the first chamber, and a third chamber partitioned from the first chamber or the second chamber.
A first chamber, a second chamber, and a fourth chamber, which is partitioned from any of the first chamber, the second chamber, and the third chamber as desired, and a communicable portion is formed between the first chamber and the second chamber. The infusion container is provided with a closed drug solution outlet communicating with the chamber or the second chamber.

A medicine is contained in each chamber of the infusion container. The communicable portion is, for example, a weak seal portion formed on the whole or a part of the communicable partition wall that partitions each chamber. The communicable portion may be, for example, a rupturable flow path blocker provided in a partition wall that partitions the infusion container, and further presses one chamber of the infusion container that contacts the communicable portion from the outside. Therefore, it is preferable that the chamber communicates with another adjacent chamber.

That is, according to the present invention, (1) a trace metal and an iodine ion are isolated and contained in an infusion container in the substantial absence of oxygen. (2) A transfusion container, which is air-permeable and is enclosed in a gas barrier outer bag in the substantial absence of oxygen, and is a partition means capable of communicating with the transfusion container. (1) A nutritional infusion preparation according to (1) above, which comprises a plurality of compartments, and (3) an amino acid-containing solution in the first chamber of the infusion container, a sugar-containing solution in the second chamber, and a third chamber. A solution containing a trace amount of metal is housed in each of the chambers, and the solution in the first chamber and / or the second chamber further contains iodine ions. The condition that does not exist is
It is achieved by enclosing the oxygen absorber in an outer bag,
Alternatively, and / or by introducing an inert gas into the outer bag, the nutritional infusion preparation according to any one of the above (1) to (3), (5) The trace metal is copper. The nutritional transfusion preparation according to any one of (1) to (4) above, (6) the sugar is glucose, according to any one of (3) to (5) above Nutritional infusion formulation, (7) The pH of the solution stored in the first chamber is 5 to 8, the pH of the solution stored in the second chamber is 2.5 to 5, and the third chamber is stored. PH of solution
Is 4 to 6.5, and the above (3) to
The nutritional infusion preparation according to any one of (6), (8) first
The solution contained in the first chamber or the second chamber contains at least one of calcium ions and phosphorus as an electrolyte, (9) The nutritional infusion formulation described in (9) the first chamber Of the above-mentioned (3) to (8), wherein the pH of the mixed solution of the stored solution, the solution contained in the second chamber and the solution contained in the third chamber is 4 to 7. Nutritional infusion formulation according to any of the following,
(10) When the solution contained in the first chamber, the solution contained in the second chamber, and the solution contained in the third chamber are mixed, the component composition is 50 to 400 g / L of glucose,
L-leucine 0.8-10.0 g / L, L-isoleucine 0.4-7.0 g / L, L-valine 0.3-8.0 g
/ L, L-lysine 0.5 to 7.0 g / L, L-threonine 0.3 to 4.0 g / L, L-tryptophan 0.08
~ 1.5 g / L, L-methionine 0.2-4.0 g /
L, L-phenylalanine 0.4 to 6.0 g / L, L-
Cysteine 0.03 to 1.0 g / L, L-tyrosine 0.
02-1.0 g / L, L-arginine 0.5-7.0 g
/ L, L-histidine 0.3-4.0 g / L, L-alanine 0.4-7.0 g / L, L-proline 0.2-5.
0 g / L, L-serine 0.2 to 3.0 g / L, glycine 0.3 to 6.0 g / L, L-aspartic acid 0.03 to
2.0 g / L, L-glutamic acid 0-3.0 g / L, sodium 20-80 mEq / L, potassium 10-40 m
Eq / L, magnesium 2-20 mEq / L, calcium 2-20 mEq / L, phosphorus 2-20 mmol / L, chlorine 20-80 mEq / L, iron 5-100 μmol / L,
Copper 1-20 μmol / L, manganese 0-5 μmol /
L, zinc 5-150 μmol / L, iodine 0.2-5 μ
mol / L above (3) to (9)
Nutritional infusion preparation according to any one of (11), 1st chamber,
In an infusion container having a fourth chamber partitioned by a partition means capable of communicating with at least one of the second chamber and the third chamber, the solution contained in the fourth chamber is vitamin A, vitamin E, vitamin D and vitamin. The nutritional infusion preparation according to any one of (3) to (10) above, which contains one or more of K, (12) a solution contained in the first chamber, and a solution contained in the second chamber. Solution contained in the third chamber and vitamin B ₁ , biotin, vitamin C, vitamin B ₁₂ , folic acid,
One or more of pantothenic acids, vitamin B ₆ , nicotinic acids and vitamin H are contained, and the above (1
1) the nutritional infusion preparation, (13) the solution contained in the first chamber, the solution contained in the second chamber, the solution contained in the third chamber, and the solution contained in the fourth chamber The component composition when mixed with is 50 to 400 g / L of glucose,
L-leucine 0.8-10.0 g / L, L-isoleucine 0.4-7.0 g / L, L-valine 0.3-8.0 g
/ L, L-lysine 0.5 to 7.0 g / L, L-threonine 0.3 to 4.0 g / L, L-tryptophan 0.08
~ 1.5 g / L, L-methionine 0.2-4.0 g /
L, L-phenylalanine 0.4 to 6.0 g / L, L-
Cysteine 0.03 to 1.0 g / L, L-tyrosine 0.
02-1.0 g / L, L-arginine 0.5-7.0 g
/ L, L-histidine 0.3-4.0 g / L, L-alanine 0.4-7.0 g / L, L-proline 0.2-5.
0 g / L, L-serine 0.2 to 3.0 g / L, glycine 0.3 to 6.0 g / L, L-aspartic acid 0.03 to
2.0 g / L, L-glutamic acid 0-3.0 g / L, sodium 20-80 mEq / L, potassium 10-40 m
Eq / L, magnesium 2-20 mEq / L, calcium 2-20 mEq / L, phosphorus 2-20 mmol / L, chlorine 20-80 mEq / L, iron 5-100 μmol / L,
Copper 1-20 μmol / L, manganese 0-5 μmol /
L, zinc 5-150 μmol / L, iodine 0.2-5 μ
mol / L, vitamin B ₁ 0.8 to 30 mg / L, vitamin B ₂ 1.0 to 6.0 mg / L, vitamin B ₆ 1.0
~ 8.0 mg / L, Vitamin B ₁₂ 1.0-20 μg /
L, nicotinic acid amide 10 to 80 mg / L, pantothenic acids 3.0 to 30 mg / L, folic acid 100 to 800 μg /
L, Vitamin C 25-200 mg / L, Vitamin A 80
0-6500 IU / L, Vitamin D 1.0-10 μg /
L, vitamin E 2.5 to 20 mg / L, vitamin K0.
5 to 4 mg / L and biotin 15 to 120 μg / L, the nutritional infusion preparation according to (11) or (12) above, (14) in an air-permeable infusion container,
The present invention relates to a method for stabilizing iodine ions or copper ions, which is characterized in that iodine ions and copper ions are separated and accommodated in the substantial absence of oxygen.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, one embodiment of an infusion solution container containing a nutritional infusion preparation according to the present invention will be specifically described with reference to the drawings. FIG. 1 is a plan view of an infusion solution container, showing an infusion solution container having four chambers (I to IV) in an outer bag 2, and an oxygen absorber 10 is enclosed in the outer bag 2. The first chamber I is filled with an amino acid-containing solution, the second chamber II is filled with an iodine ion and sugar-containing solution, the third chamber III is filled with a trace metal-containing solution, and the fourth chamber IV is filled with a vitamin-containing solution.
A communicable portion 5 is formed in the first chamber I and the second chamber II, and by pressing the first chamber I or the second chamber II, the preparation does not come into contact with the outside air, and thus the first chamber I and the second chamber II. II is communicated. The third chamber III and the fourth chamber IV are the first chamber I.
It is hung inside and is crushed by pressing from the outside to communicate with the first chamber I. The closed drug solution outlet 9 communicating with the second chamber II is used for connection with an infusion set for injecting an internal drug solution into a patient and for injecting another drug using a syringe or the like.

An example of an infusion container containing the nutritional infusion preparation according to the present invention will be described in detail below. Each chamber of the infusion container containing the nutritional infusion preparation of the present invention is housed in an outer bag having a property of impervious to gas and liquid. Further, in order to prevent oxidative decomposition of amino acids, the infusion container is generally housed in a gas barrier outer bag together with an oxygen scavenger, but it may be filled with an inert gas if necessary. further,
When containing a photodegradable vitamin, it is preferable that the outer bag have a light-shielding property. As the material suitable for the outer bag, a film or sheet of various commonly used materials can be used, for example, ethylene / vinyl alcohol copolymer, polyvinylidene chloride, polyacrylonitrile, polyvinyl alcohol, polyamide, polyester. Examples thereof include a film or sheet containing at least one kind of gas barrier material, which can be appropriately selected and used. When the outer bag is provided with a light-shielding property, it can be carried out, for example, by subjecting the film or sheet to aluminum lamination.

As the oxygen scavenger to be sealed in the outer bag,
For example, (1) iron carbide, iron carbonyl compound, iron oxide,
Iron powder, iron hydroxide or silicon iron coated with a metal halide, (2) Alkaline earth metal hydroxide or alkaline earth metal carbonate, activated carbon and water, an anhydride of a compound having crystal water, an alkaline substance or A mixture of an alcohol compound and a nithionite salt, (3) a ferrous compound, a transition metal salt, an aluminum salt, an alkali compound containing an alkali metal or an alkaline earth metal, an alkali compound containing nitrogen, or an ammonium salt. A mixture with an alkaline earth metal sulfite, (4) a mixture of iron or zinc with sodium sulfate monohydrate or a mixture of the mixture with a metal halide, (5) iron, copper, tin, zinc or nickel; Sodium sulfate heptahydrate or decahydrate;
And a mixture of a metal halide, (6) a transition metal of the fourth period of the periodic table; tin or antimony, and a mixture with water or a mixture of the mixture and a metal halide,
(7) Sulfite of alkali metal or ammonium,
Bisulfites or pyrosulfites; transition metal salts or aluminum salts; and mixtures with water can be used. It can be appropriately selected from these known materials as desired. Also, as the oxygen absorber,
Commercially available ones can be used, and examples of such commercially available oxygen absorbers include Ageless (manufactured by Mitsubishi Gas Chemical Co., Inc.) and Modulin (manufactured by Nippon Kayaku Co., Ltd.). As the above-mentioned oxygen scavenger, if it is in powder form, it is preferable to put it in a suitable air-permeable pouch, and if it is in tablet form, it may be used as it is without packaging.

Oxygen may be removed by filling the outer bag with an inert gas, and examples of such an inert gas include helium gas and nitrogen gas.

The infusion container containing the nutritional infusion preparation of the present invention has a plurality of chambers. The material for forming each chamber may be a resin that does not cause a problem in the stability of the drug to be stored, and the portion forming the chamber having a relatively large capacity is a flexible thermoplastic resin,
For example, soft polypropylene or its copolymer, polyethylene and / or its copolymer, vinyl acetate, partially saponified polyvinyl alcohol, a mixture of polypropylene and polyethylene or polybutene, olefin resin or partially cross-linked polyolefin such as ethylene-propylene copolymer, styrene elastomer. , And polyesters such as polyethylene terephthalate,
It is possible to use a material in which a suitable material such as a soft vinyl chloride resin is mixed, or a material in which a suitable resin is mixed, or a sheet obtained by molding the above material in multiple layers including other materials such as nylon.

It is preferable that the partition wall separating the chambers allows the drug to be opened without touching the outside air by externally pressing one of the infusion containers that contacts the communicable portion during use. For example, one of the plurality of chambers of the infusion container is pressed from the outside to partly separate the partition wall from the other chamber, and by communicating with the other chamber, the drugs in both chambers are mixed.

In the infusion container 1 shown in FIG. 1, the first chamber I or the second chamber II has a larger capacity than the third chamber III or the fourth chamber IV. Such a large-capacity chamber can accommodate, for example, a high-calorie infusion solution, and the first chamber I or the second chamber II is filled with a high-concentration amino acid-containing solution or sugar-containing solution. In the present invention, the amino acid-containing solution and the sugar-containing solution are preferably filled in separate chambers. For example, when the amino acid-containing solution is filled in the first chamber I, the sugar-containing solution is filled in the second chamber. It is preferably filled in chamber II.

The amino acid contained in the amino acid-containing solution filled in the first chamber I or the second chamber II is, for example, an essential amino acid, a nonessential amino acid and / or a salt, ester or N-acyl derivative of these amino acids. And so on. Specifically, for example, L-isoleucine, L
-Leucine, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, L
-Valine, L-alanine, L-arginine, L-aspartic acid, L-cysteine, L-glutamic acid, L-histidine, L-proline, L-serine, L-tyrosine,
Examples include amino acids such as L-glycine. Further, these amino acids include inorganic acid salts such as L-arginine hydrochloride, L-cysteine hydrochloride, L-glutamine hydrochloride, L-histidine hydrochloride and L-lysine hydrochloride, L-lysine acetate and L-lysine. Organic acid salts such as malate, L-tyrosine methyl ester, L-methionone methyl ester, L-
Ester forms such as methionine ethyl ester, N-substituted forms such as N-acetyl-L-cysteine, N-acetyl-L-tryptophan and N-acetyl-L-proline,
L-tyrosyl-L-tyrosine, L-alanyl-L-tyrosine, L-arginyl-L-tyrosine, L-tyrosyl-
It may be in the form of dipeptides such as L-arginine.

The pH of the amino acid-containing solution is about 2.5 to 10, preferably by using an ordinary pH adjuster, for example, acids such as hydrochloric acid, acetic acid, lactic acid, malic acid, citric acid and alkali such as sodium hydroxide. Is preferably adjusted to about 5-8.

The amino acid is preferably mixed in the solution prepared by mixing all the solutions in the following compounding amounts (converted in free form). L-leucine about 0.4-20.0 g /
L, preferably about 0.8-10.0 g / L, L-isoleucine about 0.2-14.0 g / L, preferably about 0.4.
~ 7.0 g / L, L-valine about 0.1-16.0 g /
L, preferably about 0.3 to 8.0 g / L, L-lysine about 0.2 to 14.0 g / L, preferably about 0.5 to 7.0.
g / L, L-threonine about 0.1-8.0 g / L, preferably about 0.3-4.0 g / L, L-tryptophan about 0.04-3.0 g / L, preferably about 0. .08-
1.5 g / L, L-methionine about 0.1-8.0 g /
L, preferably about 0.2 to 4.0 g / L, L-phenylalanine about 0.2 to 12.0 g / L, preferably about 0.
4 to 6.0 g / L, L-cysteine about 0.01 to 2.0
g / L, preferably about 0.03 to 1.0 g / L, L-tyrosine about 0.01 to 2 g / L, preferably about 0.02.
1.0 g / L, L-arginine about 0.2-14.0 g /
L, preferably about 0.5-7.0 g / L, L-histidine about 0.1-8.0 g / L, preferably about 0.3-4.
0 g / L, L-alanine about 0.2-14.0 g / L, preferably about 0.4-7.0 g / L, L-proline about 0.
1 to 10.0 g / L, preferably about 0.2 to 5.0 g / L
L, L-serine about 0.1-6.0 g / L, preferably about 0.2-3.0 g / L, glycine about 0.1-12.0 g
/ L, preferably about 0.3 to 6.0 g / L, L-aspartic acid about 0.01 to 4.0 g / L, preferably about 0.0
3 to 2.0 g / L, L-glutamic acid about 0 to 6.0 g /
L, preferably about 0 to 3.0 g / L is preferably blended.

The sugar contained in the sugar-containing solution to be filled in the first chamber I or the second chamber II may be one conventionally used for various infusions, for example, monosaccharides such as glucose and fructose, and maltose. Disaccharides such as Of these, reducing sugars such as glucose, fructose, and maltose are preferable, and glucose is particularly preferable in terms of blood sugar control. These reducing sugars may be used as a mixture of two or more, and a mixture obtained by adding sorbitol, xylitol, glycerin or the like to these reducing sugars may be used.

The sugar-containing solution has a pH of about 2 by appropriately using an ordinary pH adjusting agent, for example, acids such as hydrochloric acid, acetic acid, lactic acid, malic acid, citric acid and alkali such as sodium hydroxide.
~ 6, preferably about 2.5-5

These sugars are contained in a solution obtained by mixing all the solutions in an amount of about 20 to 800 g / L, preferably about 50 to 400.
It is preferable to mix them so as to be g / L.

The above amino acid-containing solution and / or sugar-containing solution further contains iodide ions. Examples of the iodine ion supply source include potassium iodide and sodium iodide, and potassium iodide is preferably used.

In the infusion container 1 shown in FIG. 1, it is preferable that a trace amount metal-containing solution is filled in the third chamber III which is divided from the first chamber I or the second chamber II. The third chamber III can be housed and used in the first chamber I or the second chamber II. As a storage method, for example, the third chamber III may be suspended in the liquid in the first chamber I or the second chamber II, but the end of the peripheral seal portion of the third chamber III is stored on the side (first It is preferable to hang it by sandwiching and sealing it in the peripheral edge of the chamber I or the second chamber II). In this case, in order to facilitate sealing, the material of the chamber containing the trace amount metal-containing solution is generally the same as the material of the innermost layer of the chamber on the containing side. The chamber containing the trace amount of metal-containing solution in the above case is provided with an easily-openable seal or a wall thickness of 100 μm or less so that the chamber can be opened from the outside of the chamber by opening when used. Preferably.

Examples of the trace metals include copper, iron, manganese, zinc and the like. Iron is preferably used as a colloid, and copper, manganese and zinc are preferably dissolved in water and filled. However, manganese and zinc can also be used as a mixture with an amino acid-containing solution or a sugar-containing solution. In the trace metal-containing solution, examples of the copper source include copper sulfate, etc., and about 0.5 to 40 μmol / L, preferably about 1 to 20 μm in a solution obtained by mixing all the solutions.
It is preferable to mix them so as to be ol / L. Examples of the iron supply source include ferric chloride, ferric sulfate, etc., and about 2 to 200 μm in a solution obtained by mixing all the solutions.
It is preferable to mix it so as to be ol / L, preferably about 5 to 100 μmol / L. Examples of the manganese source include manganese chloride, manganese sulfate, etc., and about 0 to 10 μmol in a solution obtained by mixing all the solutions.
/ L, preferably about 0 to 5 μmol / L. Examples of the zinc source include zinc chloride, zinc sulfate, etc., and about 2 to 300 μmol / L, preferably about 5 in a solution obtained by mixing all the solutions.
It is preferable to mix it so as to be about 150 μmol / L.

The trace metal-containing solution is a conventional pH adjusting agent,
For example, acid such as hydrochloric acid, acetic acid, lactic acid, malic acid, citric acid, etc. and alkali such as sodium hydroxide may be used to adjust pH.
It is preferably adjusted to about 3.5 to 7.5, preferably about 4 to 6.5.

The above-mentioned sugar-containing solution, amino acid-containing solution or trace metal-containing solution may contain an electrolyte. Examples of such an electrolyte include sodium,
Water-soluble salts of inorganic components such as potassium, magnesium, calcium, chlorine, phosphorus, for example, chlorides, sulfates, acetates,
Examples thereof include gluconate, lactate, and glycerophosphate. Examples of the sodium ion source include sodium chloride, sodium acetate, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium sulfate, sodium lactate, and the like. It is preferable that the amount is 10 to 160 mEq / L, preferably about 20 to 80 mEq / L. As the potassium ion source, for example, potassium chloride, potassium acetate, potassium citrate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium sulfate,
Calcium lactate and the like can be mentioned, and about 5 to 80 mEq / L, preferably about 10 to 4 in a solution obtained by mixing all the solutions.
It is preferable that the compounding amount be 0 mEq / L. Examples of the calcium ion source include calcium chloride,
Calcium gluconate, calcium pantothenate, calcium lactate, calcium acetate and the like can be mentioned, and it is added to a solution obtained by mixing all the solutions so as to be about 1 to 40 mEq / L, preferably about 2 to 20 mEq / L. preferable.

Examples of the magnesium ion source include magnesium sulfate, magnesium chloride, magnesium acetate, etc., and about 1 to 40 mEq / L, preferably about 2 to 20 mEq / L in a mixed solution of all the solutions.
It is preferable to mix them so that Examples of the phosphorus source include sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium glycerophosphate, etc., and about 1 to 40 mmol / L, preferably about 2 to 20 mmol / L in a solution obtained by mixing all the solutions. It is preferable to mix them so that Examples of the chlorine ion source include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like, and about 10 to 160 mEq / L, preferably about 20 to 80 m in a solution obtained by mixing all the solutions.
It is preferable to mix them so as to be Eq / L.

Regarding calcium ions and phosphorus of the above electrolytes, it is preferable to mix only one of the two when filling the same chamber with the amino acid-containing solution.
In addition, when filling the same chamber as the sugar-containing solution, both the calcium ion source and the phosphorus source may be filled together.

When the above-mentioned amino acid-containing solution, sugar-containing solution and trace metal-containing solution are mixed, the pH of the solution is about 2
-10, preferably about 4-7.

In the present invention, the fat-soluble vitamin solution may be further contained in the fourth chamber IV if desired. Examples of such fat-soluble vitamins include vitamin A, vitamin D,
Vitamin E is mentioned, and Vitamin K can be blended if necessary. Examples of vitamin A include ester forms such as palmitate and acetate. Examples of vitamin D include vitamin D ₁ , vitamin D ₂ , vitamin D ₃ (cholecalciferol) and active forms thereof (hydroxy derivatives). Examples of vitamin E (tocopherol) include ester forms such as acetic acid ester and succinic acid ester. Examples of vitamin K (phytonadione) include derivatives such as phytonadione, menatetrenone, and menadione.

These fat-soluble vitamins contain approximately 400 to 13,000 vitamin A in a solution obtained by mixing all the solutions.
IU / L, preferably about 800-6500 IU / L, vitamin D about 0.5-20 μg / L, preferably about 1.
0-10 μg / L, Vitamin E about 1.0-40 mg /
L, preferably about 2.5-20 mg / L, vitamin K about 0.2-8 mg / L, preferably about 0.5-4 mg / L.
It is preferable to blend L.

Further, water-soluble vitamins are added to the first chamber and the second chamber.
The chamber, the third chamber, or the fourth chamber may be housed in the same chamber. Examples of such water-soluble vitamins include vitamin B ₁ , vitamin B ₂ , folic acid, biotin, vitamin C,
Vitamin ₁₂ , pantothenic acids, vitamin B ₆ , nicotinic acids, vitamin H and the like can be mentioned. Such vitamins may be derivatives, specifically vitamin B ₁
Examples thereof include thiamine hydrochloride, prosultiamine, octothiamine and the like. As vitamin B ₂ ,
Examples thereof include phosphoric acid ester, sodium salt thereof, flavin mononucleotide, flavin adenine dinucleotide and the like. Examples of vitamin C include ascorbic acid and sodium ascorbate. In addition to the free form, pantothenic acids include calcium salt and the form of panthenol which is a reduced form. Examples of vitamin B ₆ include salt forms such as pyridoxine hydrochloride. Examples of the nicotinic acids include nicotinic acid and nicotinic acid amide.
Examples of vitamin B ₁₂ include cyanocobalamin.

The above vitamins are preferably blended in the following blending ratio in a solution obtained by mixing all the solutions. Vitamin B ₁ about 0.4-60 mg / L, preferably about 0.8
~ 30 mg / L, Vitamin B ₂ about 0.5-12 mg /
L, preferably about 1.0-6.0 mg / L, vitamin B
₆ about 0.5-16 mg / L, preferably about 1.0-8.
0 mg / L, Vitamin B ₁₂ about 0.5-40 μg / L,
Preferably about 1.0 to 20 μg / L, nicotinamide about 5.0 to 160 mg / L, preferably about 10 to 80 m
g / L, pantothenic acids about 1.5-60 mg / L, preferably about 3.0-30 mg / L, folic acid about 50-160 μ
g / L, preferably about 100-800 μg / L, vitamin C about 12.5-400 mg / L, preferably about 25-
200 mg / L, biotin about 7.5-240 μg / L,
It is preferable to add about 15 to 120 μg / L.

When the nutritional infusion preparation of the present invention is administered to a patient, the outer bag is broken and the first chamber, the second chamber and the third chamber, or the first chamber, the second chamber, the third chamber and the fourth chamber are separated. The chemicals in each chamber are mixed by communicating with each other.

[0037]

Example 1 Glucose and an electrolyte solution were dissolved in distilled water for injection, the pH was adjusted to 4.4 with acetic acid, and the solution was filtered to prepare a solution (A) having the composition shown in Table 1. did. Further, each crystalline amino acid and electrolyte were dissolved in distilled water for injection, adjusted to pH 6.5 with acetic acid, and then filtered to prepare solutions (B) having the compositions shown in Tables 2 and 3. In addition, sodium bisulfite was added to the solution (B) as a stabilizer so that the concentration was 50 mg / L. Separately, a predetermined amount of ferric chloride was added to the distilled water solution for injection of sodium chondroitin sulfate while alternately adding the distilled water solution for injection of ferric chloride and the distilled water solution for injection of sodium hydroxide. . After adding a predetermined amount of copper sulfate and manganese chloride to this solution, the pH was adjusted to 5.3 with sodium hydroxide or hydrochloric acid, and the liquid volume was adjusted with distilled water for injection to prepare a solution having the composition shown in Table 4. (C) was prepared. The sodium chondroitin sulfate was added so that the concentration was 2.5 g / L. 2 mL of the solution (C) was filled in a pouch formed of a polyethylene film having a thickness of 50 μm and welded. This pouch was sandwiched in advance in a polyethylene container first chamber I as a third chamber III in FIG. Each of the first chamber I and the second chamber II was separately filled with 600 mL of the solution (A) and 300 mL of the solution (B) under nitrogen substitution, sealed, and then subjected to high temperature steam sterilization according to a conventional method. , Got an infusion.
This was packaged in a light-shielding nylon multilayer bag together with an oxygen scavenger (trade name: Ageless, manufactured by Mitsubishi Gas Chemical Co., Inc.). In addition,
In this embodiment, the fourth chamber IV shown in FIG. 1 is omitted.

Example 2 Glucose and an aqueous electrolyte solution were dissolved in distilled water for injection and the pH was adjusted to 4.4 with acetic acid to prepare a sugar electrolyte solution. Further, vitamin B ₁ (thiamine hydrochloride), vitamin B ₆ (pyridoxine hydrochloride), vitamin B ₁₂ (cyanocobalamin), panthenol and biotin are dissolved in distilled water for injection, and this is mixed with the above-mentioned sugar electrolyte solution and then filtered. Then, a solution (A) having the composition shown in Table 1 was prepared. Further, each crystalline amino acid, nicotinic acid amide, folic acid, and electrolyte were dissolved in distilled water for injection, the pH was adjusted to 6.0 with acetic acid, and then filtered to obtain a solution (B) having the composition shown in Tables 2 and 3. Was prepared. In addition, sodium bisulfite was added to the solution (B) as a stabilizer so as to have a concentration of 50 mg / L. Separately, vitamin A (retinol palmitate), vitamin D ₃ (cholecalciferol), vitamin E (tocopherol acetate) and vitamin K (phytonadione) were added to polysorbate 80 (concentration in solution (D) 10 g / L) and Polysorbate 20
(Solubilized in solution (D) at a concentration of 2 g / L), dissolved in distilled water for injection, and further vitamin B ₂ (sodium riboflavin phosphate) and vitamin C (ascorbic acid)
Was added to adjust the pH to 6 with sodium hydroxide and then filtered to prepare a solution (D) having the composition shown in Table 5. Separately, in the same manner as in Example 1, a solution (C) having the composition shown in Table 4 was prepared. Two small bags molded from a polyethylene film having a thickness of 50 μm were filled with 4 mL of the solution (C) and 4 mL of the solution (D) and welded. These pouches, like the third chamber III and the fourth chamber IV shown in FIG. 1,
The polyethylene container was sandwiched in the first chamber I. The first chamber I and the second chamber II were separately filled with 600 mL of the solution (A) and 300 mL of the solution (B) under nitrogen substitution, and after sealing, high-pressure steam sterilization was performed according to a conventional method to obtain an infusion solution. Got This was packaged in a light-shielding nylon multilayer bag together with an oxygen scavenger (trade name: Ageless, manufactured by Mitsubishi Gas Chemical Co., Inc.).

[0039]

[Table 1]

[0040]

[Table 2]

[0041]

[Table 3]

[0042]

[Table 4]

[0043]

[Table 5]

[Test Example 1] Stability Test An infusion preparation containing copper ions and iodine ions in the same chamber and an infusion preparation contained in different chambers were prepared and stored at 60 ° C. for 2 to 4 weeks, The changes in the stability of trace metals were compared.

(1) When copper ion and iodine ion are put in the same chamber: Amino acid-containing solution, glucose-containing solution and copper ion are prepared in the same manner as in Example 1 except that potassium iodide is added to the solution (C). An infusion preparation was prepared by adjusting the contained trace metal solution. The infusion preparation was stored at 60 ° C. for 2 weeks, and changes in trace metal stability at this time are shown in Table 6.

[0046]

[Table 6]

(2) When copper ion and iodine ion are placed in separate chambers Amino acid-containing solution, glucose-containing solution and copper ion are prepared in the same manner as in Example 1 except that potassium iodide is added to the solution (B). An infusion preparation was prepared by adjusting the contained trace metal solution. The infusion preparation was stored at 60 ° C. for 2 to 4 weeks, and changes in trace metal stability at this time are shown in Table 7.

[0048]

[Table 7]

(3) When Copper Ion and Iodine Ion are Separated from Separate Chambers In the same manner as in Example 1, an amino acid-containing solution, a glucose-containing solution and a copper ion-containing trace metal solution were prepared to prepare an infusion preparation. The infusion preparation was stored at 60 ° C. for 2 to 4 weeks, and changes in trace metal stability at this time are shown in Table 8.

[0050]

[Table 8]

From Tables 6 to 8, when the copper ion and the iodine ion were housed in the same chamber, crystals were observed after 2 weeks and the ion content in the infusion preparation was decreased. Further, when the copper ion and the iodine ion were stored in separate chambers, the decrease in the ion content was less than that in the case where they were stored in the same chamber.

[0052]

INDUSTRIAL APPLICABILITY The infusion container of the present invention can provide an infusion preparation which does not cause precipitation under the condition that oxygen is not present in the outer bag by filling the trace metal element and the iodine ion in separate containers. it can. Further, by using the infusion container of the present invention, the complexity of the mixing operation during administration of the infusion formulation, the problem of bacterial contamination during mixing, etc. can be solved, and each infusion formulation can be simply and aseptically mixed. it can.

[Brief description of drawings]

FIG. 1 is a plan view of an embodiment of an infusion container according to the present invention.

[Explanation of symbols]

1 infusion container 2 outer bag 5 Communicatable section 9 Chemical outlet 10 oxygen absorber I Infusion container first chamber II Second chamber of infusion container III Third chamber of infusion container IV infusion container fourth chamber

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/198 A61K 31/355 31/355 31/375 31/375 31/4188 31/4188 31/4415 31 / 4415 31/455 31/455 31/51 31/51 31/525 31/525 31/59 31/59 31/7004 31/7004 31/714 31/714 33/06 33/06 33/14 33/14 33/26 33/26 33/30 33/30 33/32 33/32 33/34 33/34 33/42 33/42 A61P 3/02 A61P 3/02 A61J 1/00 351A (72) Inventor Jun Kaga 2-11, Sannomiya, Ejiri character, Kitajima-cho, Itano-gun, Tokushima Prefecture (72) Inventor Hidekatsu Shoji 1-10 Fuku term, Kitajima-cho, Kita-cho, Itano-gun, Tokushima Prefecture 4C086 AA01 AA02 BA09 BA18 BC18 BC19 BC83 CB09 CB28 CB28 DA15 DA39 EA01 HA01 HA02 HA03 HA04 HA09 HA10 HA11 HA19 HA24 MA03 MA04 MA08 MA09 MA17 MA66 NA03 ZC21 4C206 AA01 AA02 CA10 CB28 FA53 GA05 GA36 KA03 MA03 MA04 MA10 MA13 MA14 MA17 MA28 MA30 MA37 MA86 NA03 ZC21

Claims (14)

[Claims] 1. A nutritional infusion preparation containing trace metals and iodine ions, characterized in that trace metals and iodine ions are isolated and contained in an infusion container in the substantial absence of oxygen. 2. A multi-chamber chamber in which the infusion container is enclosed in a gas-barrier outer bag that is air permeable and substantially in the absence of oxygen, and the infusion container is defined by partition means that can communicate with each other. The nutritional infusion preparation according to claim 1, which comprises: 3. The solution of the first chamber and / or the second chamber, wherein the first chamber of the infusion container contains an amino acid-containing solution, the second chamber contains a sugar-containing solution, and the third chamber contains a trace metal-containing solution. 3. The nutritional infusion preparation according to claim 2, further comprising iodine ion. 4. The oxygen-free condition is achieved by enclosing a deoxidizer in the outer bag and / or by introducing an inert gas into the outer bag. The nutritional infusion preparation according to any one of claims 1 to 3. 5. The nutritional infusion preparation according to claim 1, wherein the trace metal is copper. 6. The nutritional infusion preparation according to any one of claims 3 to 5, wherein the sugar is glucose. 7. The solution contained in the first chamber has a pH of 5
~ 8, the pH of the solution contained in the second chamber is 2.5 ~
5, and the pH of the solution stored in the third chamber is 4 to
It is 6.5, The nutritional infusion formulation in any one of Claims 3-6 characterized by the above-mentioned. 8. The nutritional infusion preparation according to claim 7, wherein the solution contained in the first chamber or the second chamber contains at least one of calcium ions and phosphorus as an electrolyte. 9. The pH of the mixed solution of the solution contained in the first chamber, the solution contained in the second chamber and the solution contained in the third chamber is 4 to 7. The nutritional infusion preparation according to any one of claims 3 to 8. 10. The composition of components when the solution contained in the first chamber, the solution contained in the second chamber, and the solution contained in the third chamber are mixed is 50 to 400 g of glucose.
/ L, L-leucine 0.8-10.0 g / L, L-isoleucine 0.4-7.0 g / L, L-valine 0.3-
8.0 g / L, L-lysine 0.5 to 7.0 g / L, L-
Threonine 0.3-4.0 g / L, L-tryptophan 0.08-1.5 g / L, L-methionine 0.2-4.
0 g / L, L-phenylalanine 0.4 to 6.0 g /
L, L-cysteine 0.03-1.0 g / L, L-tyrosine 0.02-1.0 g / L, L-arginine 0.5-
7.0 g / L, L-histidine 0.3 to 4.0 g / L,
L-alanine 0.4 to 7.0 g / L, L-proline 0.
2 to 5.0 g / L, L-serine 0.2 to 3.0 g / L,
Glycine 0.3 to 6.0 g / L, L-aspartic acid 0.03 to 2.0 g / L, L-glutamic acid 0 to 3.0
g / L, sodium 20-80 mEq / L, potassium 1
0-40 mEq / L, magnesium 2-20 mEq /
L, calcium 2-20 mEq / L, phosphorus 2-20 mm
ol / L, chlorine 20-80 mEq / L, iron 5-100 μ
mol / L, copper 1 to 20 μmol / L, manganese 0 to 5
The nutritional infusion preparation according to any one of claims 3 to 9, wherein the nutritional infusion formulation is μmol / L, zinc 5-150 μmol / L, and iodine 0.2-5 μmol / L. 11. An infusion container having a fourth chamber partitioned by a partition means capable of communicating with at least one of the first chamber, the second chamber and the third chamber, wherein the solution contained in the fourth chamber is a vitamin. 4. It contains at least one of A, vitamin E, vitamin D and vitamin K.
10. The nutritional infusion preparation according to any one of 10 to 10. 12. A solution contained in the first chamber, a solution contained in the second chamber, or a solution contained in the third chamber further contains vitamin B ₁ , biotin, and vitamin C. , Vitamin B ₁₂ , folic acid, pantothenic acids, vitamin B ₆ , nicotinic acids and vitamin H 1
The nutritional infusion preparation according to claim 11, containing the above. 13. The solution contained in the first chamber, the second chamber
Solution stored in the third chamber and the solution stored in the third chamber
And component set when the solutions contained in the fourth chamber are mixed
Glucose 50-400g / L, L-leucine 0.8
~ 10.0 g / L, L-isoleucine 0.4-7.0 g
/ L, L-valine 0.3 to 8.0 g / L, L-lysine
0.5-7.0 g / L, L-threonine 0.3-4.0
g / L, L-tryptophan 0.08 to 1.5 g / L,
L-methionine 0.2-4.0 g / L, L-phenylene
Lanine 0.4-6.0 g / L, L-cysteine 0.03
~ 1.0 g / L, L-tyrosine 0.02-1.0 g / L
L, L-arginine 0.5-7.0 g / L, L-hist
Gin 0.3-4.0 g / L, L-alanine 0.4-7.
0 g / L, L-proline 0.2 to 5.0 g / L, L-se
Phosphorus 0.2 to 3.0 g / L, glycine 0.3 to 6.0 g
/ L, L-aspartic acid 0.03 to 2.0 g / L, L
-Glutamic acid 0-3.0 g / L, sodium 20-8
0mEq / L, potassium 10-40mEq / L, Magne
Sium 2 to 20 mEq / L, calcium 2 to 20 mEq
/ L, phosphorus 2 to 20 mmol / L, chlorine 20 to 80 mE
q / L, iron 5-100 μmol / L, copper 1-20 μmo
1 / L, manganese 0-5 μmol / L, zinc 5-150
μmol / L, iodine 0.2-5 μmol / L, vitamin
B ₁0.8-30mg / L, vitamin B_Two1.0 ~
6.0 mg / L, vitamin B₆1.0-8.0 mg /
L, vitamin B₁₂1.0-20 μg / L, nicotinic acid
Amide 10 to 80 mg / L, pantothenic acids 3.0 to 3
0 mg / L, folic acid 100-800 μg / L, vitamin C
25-200 mg / L, Vitamin A 800-6500I
U / L, Vitamin D 1.0-10 μg / L, Vitamin E
2.5-20 mg / L, Vitamin K 0.5-4 mg /
L, biotin 15-120 μg / L
The nutritional infusion preparation according to claim 11 or 12. 14. A method for stabilizing iodine ions or copper ions, characterized in that iodine ions and copper ions are stored separately in an air-permeable infusion container in the substantial absence of oxygen.