JP2003212767A - Infusion solution preparation containing sulfur- containing compound and trace metal element - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an infusion solution preparation having a solution containing a sulfur-containing compound, characterized in that a trace metal element exists stably. <P>SOLUTION: This infusion solution preparation is characterized by filling a solution containing a sulfur atom-containing compound in one of chambers divided with partition means capable of being communicated by pushing from the outside and housing a trace metal element-storing container in the other chamber. <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 an infusion preparation contained in an infusion container having a plurality of chambers which can be stored without being subjected to aging and can be mixed with a drug during use without being contaminated by bacteria.

[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, there is a problem that such mixed injection operation in a hospital is complicated and there is a high possibility of bacterial contamination during such mixing operation, which is unsanitary. For this reason, an infusion container having a plurality of chambers partitioned by a separable partition means has been developed and used in a hospital.

On the other hand, infusion fluids usually do not contain trace metal elements (copper, iron, zinc, manganese, etc.). Therefore, if the infusion fluid is administered for a long period of time, the patient's lips may crack or hematopoiesis may be impaired. A so-called trace metal element deficiency develops. If trace amounts of metal elements are stored in a state of being mixed with an infusion solution, a chemical reaction causes quality deterioration. For this reason, in the current situation, in hospitals, trace metal elements are still mixed just before the infusion is administered despite the problem of bacterial contamination.

In view of the above situation, the present inventors have used an infusion container having a plurality of chambers defined by partition means which can communicate with each other by pressing from the outside, and use trace amounts of metallic elements without possibility of bacterial contamination during use. We have begun research on the creation of an infusion formulation that can be mixed and has excellent storage stability. The present inventors attempted to store an amino acid infusion solution containing a sulfur-containing amino acid such as cysteine or cystine and a trace metal element separately from each other. However, when an amino acid infusion solution containing a sulfur-containing amino acid is filled in one chamber and a trace metal element storage container is housed in the same chamber, the amino acid infusion solution and the trace metal element are contained, but the trace metal element is contained. It was found that the problem that the solution is unstable occurs. The materials constituting the chamber and the trace metal element storage container were variously changed and studied, but the trace metal element solution could not be stabilized as long as it was a resin material that was normally available.

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention to provide an infusion preparation having a solution containing a sulfur-containing compound characterized in that a trace amount of metal element is stably present.

[0006]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the present inventors have found that in a multi-compartment infusion container which is partitioned by separable partition means, a sulfur atom is contained in one chamber. A solution containing a compound containing
By storing the trace metal element storage container in another chamber,
We have obtained the unexpected finding that a solution containing a trace amount of metal element is stable. The present inventors have further studied and completed the present invention.

That is, the present invention provides: (1) In an infusion container having a plurality of chambers defined by partition means which can communicate with each other by pressing from the outside, a solution containing a compound containing a sulfur atom is contained in one chamber. An infusion preparation characterized by being filled and containing a trace metal element storage container in another chamber, (2) A solution containing a compound containing a sulfur atom is a sulfur-containing amino acid or / and an amino acid containing a sulfite salt. An infusion, wherein the trace metal element is copper, (3) the infusion preparation according to the above (1), (3) a first chamber containing a trace metal element storage container, and a compound containing a sulfur atom. The infusion preparation according to (1) or (2) above, wherein the second chamber filled with the solution to be contained is adjacent to the second chamber via a septum means capable of communicating with each other, (4) Trace metal Contains element storage container The infusion preparation according to the above (1) to (3), wherein the infusion chamber is filled with a sugar infusion solution and / or an electrolyte infusion solution.

The present invention also provides (5) the infusion preparation according to (3) or (4), wherein a vitamin storage container is stored in the first chamber or the second chamber.
(6) The above-mentioned (1) to (5), wherein the trace metal element storage container or vitamin storage container and the chamber storing the same can communicate with each other by pressing from the outside.
(7) The infusion preparation according to (3) to (5), wherein the solution filled in the first chamber or the second chamber further contains vitamins. Regarding

Further, according to the present invention, (8) the component composition of the drug solution mixture obtained by connecting all of the plurality of chambers and storage containers by pressing from the outside has a glucose content of 50 to 40.
0 g / L, L-leucine 0.8 to 10.0 g / L, L-
Isoleucine 0-7.0 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 to 3.0 g / L, glycine 0.3 to 6.0 g / L, L-aspartic acid 0 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 2-200 μmol / L,
Copper 0.5-40 μmol / L, manganese 0-10 μmo
1 / L, zinc 2-200 μmol / L, iodine 0-5 μ
(1) to (7), characterized in that it is mol / L
The infusion preparation according to 1.

The present invention also provides (9) Vitamin B ₁ 0.4 to 30 mg / L, Vitamin B ₂ 0.5 to
6.0mg / L, vitamin _B 6 _0.5~8.0mg /
L, vitamin B ₁₂ 0.5 to 50 μg / L, nicotinic acids 5 to 80 mg / L, pantothenic acids 1.5 to 35 mg
/ L, folic acid 50-800 μg / L, vitamin C 12-2
00 mg / L, vitamin A 400-6500 IU / L,
Vitamin D 0.5 to 10 μg / L, vitamin E 1.0 to
20 mg / L, vitamin K 0.2 to 4 mg / L, biotin 5 to 120 μg / L, the infusion preparation according to (8) above.

The present invention also provides (10) storage stability of an infusion preparation, characterized in that, in the multi-chamber infusion preparation, a trace metal element storage container is stored in a room separate from the room containing the sulfur-containing amino acid solution. Method, (11) The method for storing and stabilizing an infusion preparation according to (10) above, wherein the trace metal element is copper.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the infusion preparation according to the present invention, an infusion container consisting of a plurality of chambers defined by partition means which can communicate with each other is used. The infusion container is not particularly limited, and a known container may be used. Specifically, for example, an infusion container in which a plurality of chambers are partitioned by a weak seal portion and one chamber of the infusion container is pressed from the outside so that the chamber communicates with another adjacent chamber is given as a preferable example. To be In addition, a structure in which a rupturable flow path closing body is provided in a partition wall that divides the infusion container into a plurality of chambers can also be used.

As a material for forming each chamber in the above-mentioned infusion container, any resin may be used as long as it does not cause a problem in stability of a medicine to be stored, and a portion forming a relatively large volume of the chamber is made of a flexible thermoplastic resin, for example. Soft polypropylene and copolymers thereof, polyethylene and / or copolymers thereof, vinyl acetate, partially saponified polyvinyl alcohol, mixture of polypropylene and polyethylene or polybutene, olefin resin or partially cross-linked polyolefin such as ethylene-propylene copolymer, styrene elastomer, Polyesters such as polyethylene terephthalate, soft vinyl chloride resins, or the like, or a material obtained by mixing an appropriate resin among them, or a sheet obtained by molding the above materials in multiple layers including other materials such as nylon can be used.

The infusion preparation according to the present invention is an infusion container consisting of a plurality of compartments defined by the above-mentioned separable partition means, and one of the compartments is filled with a solution containing a compound containing a sulfur atom, A feature is that a trace metal element storage container is stored in another chamber. By doing so, it is possible to stabilize trace metal elements, particularly copper ions, in an infusion preparation having a solution containing a compound containing a sulfur atom.

The above-mentioned "compound containing a sulfur atom (also referred to as a sulfur-containing compound in the present invention)" is not particularly limited, but examples thereof include sulfur-containing amino acids such as cysteine and cystine. In addition, examples of such a compound include a sulfite which is used as a stabilizer. Examples of the sulfite, for example, sodium hydrogen sulfite,
Examples include sodium sulfite, sodium pyrosulfite, sodium thiosulfite, Rongalit, and the like. The infusion preparation of the present invention may contain the above-mentioned sulfur-containing compound alone, or may contain two or more kinds of sulfur-containing compounds. The content of the above-mentioned sulfur-containing compound is not particularly limited, but in the case of a sulfur-containing amino acid, the content thereof is about 0.1-1.
It is preferably 0 g / L, and in the case of sulfite, its content is preferably about 0.02-0.5 g / L.

The above "solution containing a sulfur-containing compound" is
As long as the above-mentioned sulfur-containing compound is included, it is not particularly limited, but an amino acid infusion solution containing a sulfur-containing amino acid or / and a sulfite is preferable. As the amino acid infusion,
Known ones may be used. For example, the amino acids contained in the amino acid infusion solution include essential amino acids, non-essential amino acids and / or salts, esters or N-acyl forms of these amino acids. More 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 or L-glycine. In addition, these amino acids are L-
Inorganic acid salts such as arginine hydrochloride, L-cysteine hydrochloride, L-glutamine hydrochloride, L-histidine hydrochloride and L-lysine hydrochloride, and organic acids such as L-lysine acetate and L-lysine malate. Salt, L-tyrosine methyl ester, L
-Methionone methyl ester, ester form such as L-methionine ethyl ester, N-substituted form such as N-acetyl-L-cysteine, N-acetyl-L-tryptophan, N-acetyl-L-proline, L-tyrosyl- L-
It may be in the form of dipeptides such as tyrosine, L-alanyl-L-tyrosine, L-arginyl-L-tyrosine and L-tyrosyl-L-arginine.

Amino acids are preferably mixed in the solution prepared by mixing all the solutions in the following compounding amounts (converted in free form). That is, L-leucine about 0.8 to 1
0.0 g / L, preferably about 2.0-5.0 g / L, L
-Isoleucine from about 0 to 7.0 g / L, preferably about 1.
0-3.0 g / L, L-valine about 0.3-8.0 g /
L, preferably about 1.0 to 3.0 g / L, L-lysine about 0.5 to 7.0 g / L, preferably about 1.5 to 4.5 g
/ L, L-threonine about 0.3 to 4.0 g / L, preferably about 0.5 to 2.0 g / L, L-tryptophan about 0.08 to 1.5 g / L, preferably about 0.2. ~ 1.0
g / L, L-methionine about 0.2 to 4.0 g / L, preferably about 0.5 to 1.5 g / L, L-phenylalanine about 0.4 to 6.0 g / L, preferably about 1. 0-2.5
g / L,

L-cysteine about 0.03 to 1.0 g /
L, preferably about 0.15-0.5 g / L, L-tyrosine about 0.02-1.0 g / L, preferably about 0.05-
0.20 g / L, L-arginine about 0.5 to 7.0 g /
L, preferably about 1.5-3.5 g / L, L-histidine about 0.3-4.0 g / L, preferably about 0.5-2.
5 g / L, L-alanine about 0.4 to 7.0 g / L, preferably about 1.0 to 3.0 g / L, L-proline about 0.2
~ 5.0 g / L, preferably about 0.5-2.0 g / L,
L-serine about 0 to 3.0 g / L, preferably about 0.5 to
1.5 g / L, glycine about 0.3 to 6.0 g / L, preferably about 0.5 to 2.5 g / L, L-aspartic acid about 0 to 2.0 g / L, preferably about 0.1. ~ 1.0 g /
L, L-glutamic acid is preferably blended in an amount of about 0 to 3.0 g / L, preferably about 0.1 to 1.0 g / L.

The pH of the above amino acid infusion solution is about 2.5 to 10, preferably by 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. Is preferably adjusted to about 5-8.

In the infusion preparation of the present invention, a container containing a trace metal element containing a liquid containing a trace metal element (hereinafter, also referred to as "a trace metal element-containing solution") is filled with a solution containing a sulfur-containing compound. It is stored in a room different from the room. As a method for accommodating the trace metal element storage container, for example, the trace metal element storage container may be suspended in the liquid in the room, but the end of the peripheral edge seal portion of the trace metal element storage container is sandwiched between the peripheral edges of the storage chamber. It is preferable to suspend by sealing with. In this case, in order to facilitate sealing, the material of the chamber containing the trace metal element-containing solution is generally the same as the material of the innermost layer of the trace metal element storage container. Moreover, it is preferable that the trace metal element storage container can communicate with the chamber that stores the trace metal element storage container.
As a means therefor, a known means may be used. Specifically, as described above, the weak metal seal portion or the wall thickness of the container containing the trace metal element is about 100 μm.
It is preferable that the structure is partitioned by a thin film having a thickness of m or less, and the trace metal element containing container is pressed from the outside so that the container communicates with the chamber containing it. Further, the trace metal element storage container may have a rupturable flow path closing body in a partition wall with a chamber storing the trace metal element storage container.

Examples of the trace metal elements include copper,
Examples include iron, manganese, and zinc. The trace metal element in the trace metal element accommodating container may be a trace metal element or a compound containing the trace metal element, a solution or a suspension containing them. Further, if desired, other components may be present in the trace metal element storage container. It is preferable that iron is colloidal, and copper, manganese, and zinc are dissolved in water in the trace metal element storage container to fill the trace metal element storage container. 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 element-containing solution, examples of the copper source include copper sulfate, etc., and about 0.5 to 40 μmol / in a solution obtained by mixing all the solutions in the preparation.
L, preferably about 1 to 20 μmol / L is preferably blended. Examples of the iron source include ferric chloride, ferric sulfate, etc., and about 2 to 200 μmol / L, preferably about 5 to 100 μmol / L in a solution obtained by mixing all the solutions in the formulation. It is preferable to mix them as follows. Examples of the manganese supply source include manganese chloride and manganese sulfate, which are mixed so as to be about 0 to 10 μmol / L, preferably about 0 to 5 μmol / L in a solution obtained by mixing all the solutions in the preparation. Preferably. As a source of zinc, for example, zinc chloride,
Examples include zinc sulfate, etc., and about 2 to 300 μmol / L, preferably about 5 in a solution obtained by mixing all the solutions in the formulation.
It is preferable to mix it so as to be about 150 μmol / L.

The pH of the trace metal element-containing solution is about 4.0.
˜7.5, preferably about 4.5-6.5.

The above-mentioned "chamber for accommodating a trace metal element storage container" may or may not be filled with a solution. Above all, it is preferable that either the sugar infusion solution or the electrolyte infusion solution or a mixture thereof is stored in the chamber.

As the above-mentioned sugar transfusion, known ones may be used. The sugar contained in such a sugar infusion solution may be one conventionally used for various infusion solutions, such as glucose,
Examples include monosaccharides such as fructose and disaccharides such as maltose. 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 above-mentioned sugar infusion solution has a pH of about 2 to 6, preferably pH of about 2 to 6, preferably 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. It is preferably adjusted to about 3.5-5. In addition, about 50 to 400 g of these sugars are contained in a solution obtained by mixing all the solutions in the infusion preparation of the present invention.
/ L, preferably about 100 to 200 g / L. Furthermore, the above-mentioned sugar infusion solution may contain the following electrolyte in the following concentration.

As the electrolyte infusion solution, a known one may be used. As the electrolyte contained in such an electrolyte infusion solution,
Examples thereof include water-soluble salts of inorganic components such as sodium, potassium, magnesium, calcium, chlorine and phosphorus, such as chloride, sulfate, acetate, 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 or sodium lactate. A solution obtained by mixing all the solutions. About 10 to 160mE
It is preferable that the amount is q / L, preferably about 20 to 80 mEq / L, and more preferably about 30 to 60 mEq / L. Examples of the potassium ion source include potassium chloride, potassium acetate, potassium citrate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium sulfate, calcium lactate, and the like. 5-80 mEq / L, preferably about 10-40 mEq / L, more preferably about 15-30.
It is preferable to mix them so as to be mEq / L.

Examples of the calcium ion source include calcium chloride, calcium gluconate, calcium pantothenate, calcium lactate, calcium acetate and the like, and about 1 to 40 in a mixed solution of all the solutions.
It is preferable that the amount is mEq / L, preferably about 2 to 20 mEq / L, more preferably about 2 to 10 mEq / L. 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 mE in a solution obtained by mixing all the solutions.
It is preferable to mix q / L, more preferably about 2 to 10 mEq / L.

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 2 in a mixed solution of all the solutions. 20 mmo
It is preferable to add 1 / L, more preferably about 3 to 10 mmol / L. Examples of the chlorine ion source include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc., and about 10 to 160 mEq / L in a mixed solution of all the solutions,
It is preferable to mix it so as to be preferably about 20 to 80 mEq / L, more preferably about 30 to 60 mEq / L.

As a preferred embodiment of the infusion preparation according to the present invention, a first chamber in which a trace metal element storage container is stored,
An infusion preparation may be mentioned in which the second chamber filled with a solution containing a compound containing a sulfur atom is adjacent to the second chamber via a partition means which can communicate with each other. A specific embodiment of such an infusion preparation will be described with reference to FIG. FIG. 1 is a plan view of an infusion container that contains an infusion preparation according to the present invention. The infusion container has a first chamber (reference numeral 4 in the figure) and a second chamber (reference numeral 5 in the figure) in the outer bag 2. A communicable portion 3 is formed between the first chamber and the second chamber, and by pressing the first chamber 4 or the second chamber 5, the communicable portion 3 is separated to prevent the medicine from contacting the outside air. The chamber 4 and the second chamber 5 communicate with each other.

Further, the trace metal element storage container 6 is suspended in the first chamber 4 and is crushed by pressing from the outside to communicate with the first chamber 4. More specifically, it is suspended by sandwiching and sealing the end of the peripheral edge seal portion of the trace metal element storage container 6 in the peripheral edge of the first chamber 4.
Also, when using it, you can press it from the outside of the chamber to break the bag,
It is preferable that the trace metal element storage container is separated from the first chamber 4 by an easily-openable seal or is made of a thin film having a wall thickness of about 100 μm or less.

In the infusion preparation of this embodiment, the first chamber 4 of the infusion container shown in FIG. 1 may or may not be filled with the solution. Above all, as described above, it is preferable that the first chamber 4 is filled with a sugar infusion solution and / or an electrolyte infusion solution. Further, the trace metal element storage container 6 is filled with the trace metal element liquid as described above. Further, the second chamber 5 of the infusion container shown in FIG. 1 is filled with the solution containing the sulfur-containing compound as described above.

The infusion container shown in FIG. 1 is further provided with a closed drug solution outlet 8 which communicates with the second chamber 5 and is connected to an infusion set for injecting an internal drug solution into a patient. Further, it is used for injecting another drug using a syringe or the like.

Each chamber of the infusion container for containing the infusion preparation of the present invention is preferably housed in an outer bag 2 having a property of impervious to gas and liquid. Further, it is preferable that the oxygen scavenger 9 is contained in the gas barrier outer bag 2. By doing so, there is an advantage that it is possible to suppress the oxidative decomposition of the components of the infusion preparation of the present invention, particularly the components such as amino acids which are easily oxidized and decomposed. Instead of enclosing the oxygen absorber 9, or while enclosing the oxygen absorber 9, the outer bag 2 may be filled with an inert gas, if desired. Furthermore, when a component having poor photostability such as a photodegradable vitamin is filled, it is preferable that the outer bag have a light-shielding property.

As a material suitable for the outer bag, a generally used film or sheet of various materials can be used. For example, a film or sheet containing at least one gas barrier material such as ethylene / vinyl alcohol copolymer, polyvinylidene chloride, polyacrylonitrile, polyvinyl alcohol, polyamide and polyester 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 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. In the present invention, it is possible to appropriately select from these known substances as desired.

As the oxygen scavenger, commercially available oxygen scavengers can be used. Examples of such oxygen scavengers on the market include Ageless (manufactured by Mitsubishi Gas Chemical Co., Inc.) and Modulan (manufactured by Nippon Kayaku Co., Ltd.). To be As the oxygen absorber,
If it is a powder, it is preferable to put it in a suitable air-permeable pouch for use, and if it is a tablet, 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 preparation according to the present invention may further contain vitamins. The vitamin may be dissolved in the first chamber or the second chamber, and further, the vitamin storage container may be stored in the first chamber or the second chamber. It is preferable that such a vitamin storage container can communicate with a chamber storing the vitamin storage container by pressing from the outside. As the means, known means as described above may be used. More specifically, an infusion preparation contained in the infusion container shown in FIG. 2 or 3 can be mentioned. In the infusion container shown in FIG. 2, the vitamin storage container (reference numeral 7 in the figure), which is separate from the trace metal element storage container 6 in the first chamber 4, is exactly the same as the storage means of the trace metal element storage container 6 described above. It has been stored. Further, in the infusion container shown in FIG. 3, the vitamin storage container (reference numeral 7 in the drawing) is stored in the second chamber 5 in exactly the same manner as the storage means of the trace metal element storage container 6 described above.

The vitamin solution filled in the vitamin container may be a known one. Specifically, there is a case where the above-mentioned vitamin storage container is filled with a fat-soluble vitamin solution. Examples of the fat-soluble vitamins include vitamin A, vitamin D, and vitamin E, and vitamin K may be added if desired. 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 their active forms (hydroxy derivatives). Vitamin E
Examples of (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 about 400-6500 I of vitamin A in a solution obtained by mixing all the solutions.
U / L, preferably about 800-4000 IU / L, vitamin D (as cholecalciferol) about 0.5-1
0 μg / L, preferably about 1.0-6.0 μg / L, Vitamin E (as tocophenol acetate) about 1.0-2
0 mg / L, preferably about 2.5-12.0 mg / L,
Vitamin K (as phytonadione) about 0.2-4m
It is preferable to add g / L, preferably about 0.5 to 2.5 mg / L.

The vitamin storage container may be filled with a water-soluble vitamin together with the fat-soluble vitamin solution or instead of the fat-soluble vitamin solution. 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 or vitamin H. Such vitamin may be a derivative, and specific examples of vitamin B ₁ include thiamine hydrochloride, prosultiamine or octothiamine. Examples of vitamin B ₂ include phosphate, its sodium salt, 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-mentioned water-soluble vitamins are preferably added in the following mixing ratio in a solution obtained by mixing all the solutions. Vitamin B ₁ (as thiamine hydrochloride) about 0.4 ~
30 mg / L, preferably about 1.0-5.0 mg / L,
Vitamin _{B 2} (as a riboflavin) about 0.5-6.
0 mg / L, preferably about 0.8-4.0 mg / L, vitamin B ₆ (as pyridoxine hydrochloride) about 0.5-
8.0 mg / L, preferably about 1.0-5.0 mg / L
L, Vitamin B ₁₂ (as cyanocobalamin) about 0.5 to 50 μg / L, preferably about 1.0 to 10 μg
/ L, nicotinic acid (as nicotinic acid amide) about 5
-80 mg / L, preferably about 8-50 mg / L, pantothenic acids (as pantothenic acid) about 1.5-35 m
g / L, preferably about 3.0-20 mg / L, folic acid about 50-800 μg / L, preferably about 40-120 μg
/ L, Vitamin C (as ascorbic acid) about 12 ~
200 mg / L, preferably about 20-120 mg / L,
Biotin is about 5 to 120 μg / L, preferably about 10
It is preferably 70 μg / L.

The above-mentioned water-soluble vitamin is not limited to the vitamin container, but may be contained in the first chamber or the second chamber of the infusion container shown in FIGS.

When the infusion preparation of the present invention is administered to a patient, the outer bag is broken and a plurality of chambers, that is, in the infusion preparation shown in FIG. In the infusion preparation shown in 2 or 3, the first
The chemicals in the respective chambers are mixed by communicating the chamber, the second chamber, the trace metal element storage container, and the vitamin storage container.
In the infusion preparation of the present invention, it is preferable that the composition of the drug solution obtained by connecting all of the plurality of chambers and the storage container to each other by pressing from the outside has the following composition.

That is, glucose is about 50 to 400 g /
L, preferably about 100-200 g / L, L-leucine about 0.8-10.0 g / L, preferably about 2.0-5.
0 g / L, L-isoleucine about 0-7.0 g / L, preferably about 1.0-3.0 g / L, L-valine about 0.3-
8.0 g / L, preferably about 1.0-3.0 g / L, L
-Lysine about 0.5 to 7.0 g / L, preferably about 1.5
~ 4.5 g / L, L-threonine about 0.3-4.0 g /
L, preferably about 0.5-2.0 g / L, L-tryptophan about 0.08-1.5 g / L, preferably about 0.2.
~ 1.0 g / L, L-methionine about 0.2-4.0 g / L
L, preferably about 0.5 to 1.5 g / L, L-phenylalanine about 0.4 to 6.0 g / L, preferably about 1.0.
~ 2.5 g / L,

L-cysteine about 0.03 to 1.0 g /
L, preferably about 0.15-0.5 g / L, L-tyrosine about 0.02-1.0 g / L, preferably about 0.05-
0.20 g / L, L-arginine about 0.5 to 7.0 g /
L, preferably about 1.5-3.5 g / L, L-histidine about 0.3-4.0 g / L, preferably about 0.5-2.
5 g / L, L-alanine about 0.4 to 7.0 g / L, preferably about 1.0 to 3.0 g / L, L-proline about 0.2
~ 5.0 g / L, preferably about 0.5-2.0 g / L,
L-serine about 0 to 3.0 g / L, preferably about 0.5 to
1.5 g / L, glycine about 0.3 to 6.0 g / L, preferably about 0.5 to 2.5 g / L, L-aspartic acid about 0 to 2.0 g / L, preferably about 0.1. ~ 1.0 g /
L, L-glutamic acid is about 0 to 3.0 g / L, preferably about 0.1 to 1.0 g / L.

Further, the infusion preparation of the present invention contains the following components as an electrolyte and a trace metal element. That is, sodium about 20-80 mEq / L, potassium about 10-40 mEq / L, magnesium about 2-20 mEq.
/ L, calcium about 2-20 mEq / L, phosphorus about 2-2
0 mmol / L, chlorine about 20-80 mEq / L, iron about 2
~ 200 μmol / L, copper about 0.5-40 μmol / L
L, manganese about 0 to 10 μmol / L, zinc about 2 to 20
It is 0 μmol / L and iodine is about 0 to 5 μmol / L.

The infusion preparation according to the present invention further comprises:
It is preferable to contain the components in the following concentrations. That is,
Vitamin B₁About 0.4 to 30 (as thiamine hydrochloride)
mg / L, preferably about 1.0-5.0 mg / L, bitter
Min B_TwoAbout 0.5-6.0 m (as riboflavin)
g / L, preferably about 0.8-4.0 mg / L, vitamin
B ₆About 0.5-8.0 (as pyridoxine hydrochloride)
mg / L, preferably about 1.0-5.0 mg / L, bitter
Min B₁₂About 0.5 to 5 (as cyanocobalamin)
0 μg / L, preferably about 1.0-10 μg / L, Nico
Approximately 5-80 mg of tin acids (as nicotinamide)
/ L, preferably about 8 to 50 mg / L, pantothenic acids
About 1.5 to 35 mg / L, preferably about 3.0 to 20
mg / L, folic acid about 50-800 μg / L, preferably
About 40-120 μg / L, Vitamin C (ascorbic acid
As about 12-200 mg / L, preferably about 20
~ 120mg / L, vitamin A about 400-6500I
U / L, preferably about 800-4000 IU / L, bitter
Min D (as cholecalciferol) about 0.5-1
0 μg / L, preferably about 1.0-6.0 μg / L,
Tammine E (as tocophenol acetate) about 1.0-2
0 mg / L, preferably about 2.5-12.0 mg / L,
Vitamin K (as phytonadione) about 0.2-4.
0 mg / L, preferably about 0.5-2.5 mg / L,
Otin is about 5 to 120 μg / L, preferably about 10 to 7
It is preferably contained at 0 μg / L.

In the infusion preparation according to the present invention, it is preferable that the pH of the drug solution mixture obtained by connecting all of the plurality of chambers and the storage container to each other by pressing from the outside is about 4 to 7.

[0052]

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. Also, 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 a solution (B) having the composition shown in Table 2. 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 is adjusted to 5 with sodium hydroxide or hydrochloric acid.
The solution was adjusted to 3 and the liquid volume was adjusted with distilled water for injection to prepare a solution (C) having the composition shown in Table 3. The sodium chondroitin sulfate was added so that the concentration would be 5.0 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 (reference numeral 4 in FIG. 1) as a trace metal element storage container (reference numeral 6 in FIG. 1). In each of the first chamber 4 and the second chamber (reference numeral 5 in FIG. 1), 600 mL of the solution (A) and 300 of the solution (B) are provided.
After individually filling each mL with nitrogen substitution and sealing, the mixture was subjected to high temperature steam sterilization at 108 ° C. for 20 minutes according to a conventional method to obtain an infusion solution. 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 this way, the infusion preparation according to the present invention contained in the infusion container shown in FIG. 1 was manufactured.

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. In addition, each crystalline amino acid, nicotinic acid amide, folic acid and electrolyte were dissolved in distilled water for injection, adjusted to pH 6.0 with acetic acid and then filtered to prepare a solution (B) having the composition shown in the following table. . In addition, sodium bisulfite was added to the solution (B) as a stabilizer so as to have a concentration of 200 mg / L.

Separately, vitamin A (retinol palmitate), vitamin D ₃ (cholecalciferol), vitamin E (tocopherol acetate) and vitamin K (phytonadione) were added to polysorbate 80 (solution (D) at a concentration of 10 g). / L), polysorbate 20 (concentration 2g / L in solution (D)) and Macrogol 400
It was solubilized in (concentration of 40 g / L in solution (D)) and then dissolved in distilled water for injection. Vitamin B ₂ (sodium riboflavin phosphate), vitamin C (ascorbic acid) and D-sorbitol (concentration in solution (D) 20 g / L)
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 4. Separately, a solution (C) having the composition shown in Table 3 was prepared in the same manner as in Example 1.

Two small bags formed of a polyethylene film having a thickness of 50 μm were filled with 2 mL of the solution (C) and 2 mL of the solution (D) and welded. These pouches are provided in a polyethylene container first chamber (reference numeral in FIG. 2) such as a trace metal element storage container (reference numeral 6 in FIG. 2) and a vitamin storage container (reference numeral 7 in FIG. 2) shown in FIG. It was sandwiched in 4). The first chamber 4 and the second chamber (reference numeral 5 in FIG. 2)
To 600 mL of solution (A) and 300 mL of solution (B)
After individually filling each mL with nitrogen substitution and sealing, the mixture was subjected to high temperature steam sterilization at 108 ° C. for 20 minutes according to a conventional method to obtain an infusion solution. 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 this manner, the infusion preparation according to the present invention contained in the infusion container shown in FIG. 2 was manufactured.

Example 3 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) and panthenol were dissolved in distilled water for injection and mixed with the above-mentioned sugar electrolyte solution,
A solution (A) having the composition shown in Table 1 was prepared by filtration. In addition, each crystalline amino acid, nicotinic acid amide, folic acid and electrolyte were dissolved in distilled water for injection, adjusted to pH 6.0 with acetic acid and then filtered to prepare a solution (B) having the composition shown in the following table. . 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 D ₃ (cholecalciferol), vitamin E (tocopherol acetate) and vitamin K (phytonadione) were added to polysorbate 8
0, polysorbate 20, D-sorbitol and Macrogol 400, and then solubilized in distilled water for injection, further added vitamin C (ascorbic acid), adjusted to pH 6 with sodium hydroxide, and then filtered. A solution (D) having the composition shown in was prepared. Separately, a solution (C) having the composition shown in Table 3 was prepared in the same manner as in Example 1.

Solution (C) (2 mL) and solution (D) (4 mL) were filled in two sachets formed of a polyethylene film having a thickness of 50 μm and welded. These pouches are provided in a polyethylene container first chamber (reference numeral in FIG. 2) such as a trace metal element storage container (reference numeral 6 in FIG. 2) and a vitamin storage container (reference numeral 7 in FIG. 2) shown in FIG. It was sandwiched in 4). The first chamber 4 and the second chamber (reference numeral 5 in FIG. 2)
To 700 mL of solution (A) and 300 mL of solution (B)
After individually filling each mL with nitrogen substitution and sealing, the mixture was subjected to high temperature steam sterilization at 108 ° C. for 20 minutes according to a conventional method to obtain an infusion solution. 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 this manner, the infusion preparation according to the present invention contained in the infusion container shown in FIG. 2 was manufactured.

Example 4 Solutions (A), (B), (C)
And (D) were adjusted in exactly the same manner as in Example 3.
Solution (C) 2mL and solution (D) are respectively put in two sachets molded from a polyethylene film having a thickness of 50 μm.
2 mL was filled and welded. The pouch containing the solution (C) was sandwiched between the polyethylene container first chambers (reference numeral 4 in FIG. 3) like the trace metal element storage container (reference numeral 6 in FIG. 3) shown in FIG. . Further, a pouch containing the solution (D) was sandwiched between the polyethylene container second chamber (reference numeral 5 in FIG. 3) like the vitamin storage container (reference numeral 7 in FIG. 3) shown in FIG. . The first chamber 4 and the second chamber 5 were separately filled with 700 mL of the solution (A) and 300 mL of the solution (B) under nitrogen substitution, and after sealing, followed by a conventional method at 108 ° C. for 20 minutes, High temperature steam sterilization was performed to obtain an infusion solution. 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 this manner, the infusion preparation according to the present invention contained in the infusion container shown in FIG. 3 was manufactured.

[Comparative Example] Solutions (A), (B) and (C) were changed in composition as shown in the following table.
The adjustment was performed in exactly the same manner as in Example 1. However, solution (B)
Sodium bisulfite as a stabilizer has a concentration of 50 mg
/ 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. The pouch was sandwiched in advance in a polyethylene container second chamber (reference numeral 4 in FIG. 4) as a trace metal element storage container (reference numeral 6 in FIG. 4). Each of the first chamber 4 and the second chamber (reference numeral 5 in FIG. 4) was separately filled with 600 mL of the solution (A) and 300 mL of the solution (B) under nitrogen substitution, sealed, and then sealed by a conventional method. According to the above, high temperature steam sterilization was performed at 108 ° C. for 20 minutes to obtain an infusion solution. 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 this way, FIG.
The infusion preparation contained in the infusion container shown in was produced.

The compositions of solutions (A), (B), (C) and (D) in Examples 1 to 4 and Comparative Example are shown in the table below.

[0062]

[Table 1]

[0063]

[Table 2]

[0064]

[Table 3]

[Table 4]

[Stability Test] The infusion preparations produced in Examples 1 to 4 and Comparative Example were stored at 60 ° C. for 2 weeks. When the appearance of the container after storage was visually observed, the trace metal element-containing container was colored only in the infusion preparation of Comparative Example.

[Table 5]

[0066]

INDUSTRIAL APPLICABILITY According to the present invention, in an infusion preparation containing a sulfur-containing compound and a trace metal element, bacterial contamination can be completely eliminated when the trace metal element is mixed with the infusion solution at the time of use, and Thus, it is possible to provide an infusion preparation that can be stored without being subjected to changes with time.

[Brief description of drawings]

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

FIG. 2 is a plan view of an infusion container used in another embodiment of the infusion preparation according to the present invention.

FIG. 3 is a plan view of an infusion container used in another embodiment of the infusion preparation according to the present invention.

FIG. 4 is a plan view of an infusion container used in an infusion preparation produced in Comparative Example.

[Explanation of symbols]

1 infusion container 2 outer bag 3 communication possible parts 4 First chamber of infusion container 5 Second chamber of infusion container 6 Trace metal element container 7 Vitamin container 8 Chemical outlet 9 oxygen absorber

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/4415 A61K 31/455 31/455 31/51 31/51 31/525 31/525 31/592 31 / 592 31/7004 31/7004 31/714 31/714 33/18 33/18 33/26 33/26 33/30 33/30 33/34 33/34 A61J 1/00 351A (72) Inventor Hidekatsu Shoji Tokushima Prefecture Itano-gun Kitashima-cho Shinkirai 1-10 F-term (reference) 4C076 AA12 CC21 FF66 4C086 AA01 BA09 BA18 BC18 BC19 BC82 CB09 CB28 DA14 DA39 EA01 GA07 GA10 HA01 HA03 HA09 HA11 MA17 MA66 ZC21 4C206 AA01 CA10 MA28 CB28 FA05 MA37 NA03 ZC21

Claims (11)

[Claims] 1. An infusion container having a plurality of chambers defined by partition means which can communicate with each other by pressing from the outside, wherein one chamber is filled with a solution containing a compound containing a sulfur atom, and the other chamber is filled with the solution. An infusion preparation characterized by containing a trace metal element storage container. 2. The infusion solution according to claim 1, wherein the solution containing a compound containing a sulfur atom is an amino acid infusion solution containing a sulfur-containing amino acid or / and a sulfite, and the trace metal element is copper. Formulation. 3. A first chamber in which a trace metal element accommodating container is accommodated and a second chamber in which a solution containing a compound containing a sulfur atom is filled are adjacent to each other via a partition means which can communicate with each other. The infusion preparation according to claim 1 or 2, wherein 4. The infusion preparation according to any one of claims 1 to 3, wherein a chamber containing the trace metal element storage container is filled with a sugar infusion solution and / or an electrolyte infusion solution. 5. The vitamin storage container is stored in the first chamber or the second chamber, according to claim 3 or 4.
The infusion preparation described in. 6. The trace metal element storage container or vitamin storage container and the chamber storing the same can communicate with each other by pressing from the outside.
The infusion preparation described in. 7. The infusion preparation according to claim 3, wherein the solution filled in the first chamber or the second chamber further contains vitamins. 8. The chemical composition of the drug solution obtained by connecting all of the plurality of chambers and the storage container by pressing from the outside has a composition of glucose of 50 to 400 g / L and L-leucine of 0.8 to 10.0 g / l. L, L-isoleucine 0-7.0
g / L, L-valine 0.3 to 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 to 1.5 g / L,
L-methionine 0.2 to 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, 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 to 5.0 g / L, L-serine 0 to 3.0 g / L, glycine 0.3 to 6.0 g /
L, L-aspartic acid 0-2.0 g / L, L-glutamic acid 0-3.0 g / L, sodium 20-80 mEq
/ L, potassium 10-40 mEq / L, magnesium 2
-20 mEq / L, calcium 2-20 mEq / L, phosphorus 2-20 mmol / L, chlorine 20-80 mEq / L,
Iron 2 to 200 μmol / L, copper 0.5 to 40 μmol / L
L, manganese 0 to 10 μmol / L, zinc 2 to 300 μ
Mol / L, iodine 0-5 micromol / L, The infusion formulation of Claims 1-7 characterized by the above-mentioned. 9. Vitamin B ₁ 0.4-30 mg
/ L, vitamin B ₂ 0.5-6.0 mg / L, vitamin B ₆ 0.5-8.0 mg / L, vitamin B ₁₂ 0.5-
20 μg / L, nicotinic acids 5-80 mg / L, pantothenic acids 1.5-35 mg / L, folic acid 50-800 μg
/ L, Vitamin C12-200mg / L, Vitamin A4
00-6500 IU / L, Vitamin D 0.5-10 μg
/ L, Vitamin E 1.0-20 mg / L, Vitamin K
The infusion preparation according to claim 8, which contains 0.2 to 4 mg / L and biotin to 5 to 120 µg / L. 10. A method for preserving the stability of an infusion preparation, characterized in that in a multi-chamber infusion preparation, a trace metal element containing container is housed in a room separate from the room containing the sulfur-containing amino acid solution. 11. The method of preserving and stabilizing an infusion preparation according to claim 10, wherein the trace metal element is copper.