JPH08709A - Container of transfusion liquid containing, transfusion formulation, and synthetic high calory transfusion liquid formulation vitamin - Google Patents

Abstract

PURPOSE:To provide a container for containing a transfusion liquid useful in preparing a transfusion liquid containing sugars, amino acids, electrolytes, a fat emulsion and a vitamins. CONSTITUTION:By using a container in which two independent chambers are formed by a separation means 28, a transfusion liquid 24 containing fat emulsion, sugar and a specified vitamin is accommodated in a first chamber 22, while a transfusion liquid 25 containing amino acids, electrolytes and another specified vitamin is accommodated in a second chamber 23. When using, the separation means 28 is removed and the transfusions accommodated in the first chamber 22 and the second chamber 23 are mixed, whereby the transfusion containing sugars, amino acids, electrolytes, a fat emulsion and vitamins can be readily and aseptically prepared.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an infusion preparation containing a fat emulsion, sugar, amino acid, electrolyte and vitamins, an infusion container and an infusion preparation used for the preparation of the infusion preparation. More specifically, an infusion preparation containing a fat emulsion, sugar and a specific vitamin, an infusion preparation containing an amino acid, an electrolyte and other vitamins, and an infusion container containing the above and the infusion preparations in each individual chamber. , And a vitamin-containing total high-calorie infusion formulation prepared by mixing infusions contained in individual compartments.

[0002]

2. Description of the Related Art Conventionally, in maintaining the life of a patient, oral nutrition and tube feeding are impossible or inadequate, or even if they are possible, the digestive absorption function of the patient is In the case of extremely poor conditions, or in the case of a pathological condition in which the passage of food through the digestive tract leads to aggravation of the original disease, intravenous administration of an infusion is performed for nutritional supplementation. As such infusion preparations, sugar infusions containing reducing sugars, amino acid infusions containing essential amino acids, electrolyte infusions containing minerals, fat emulsions containing vegetable oil emulsions, mixed vitamin preparations, etc. are commercially available. These infusion preparations are appropriately mixed and used at the time of use according to the patient's symptoms and the like. However, mixing the infusion preparation during use is a complicated operation for workers, and above all, there is a problem of bacterial contamination during mixing. From such a problem, an infusion formulation in which the above various infusions are mixed in advance has been proposed, and in particular, an infusion formulation containing sugar, an amino acid, an electrolyte and a fat emulsion, which are components necessary for nutritional supplementation to a patient, It is extremely useful clinically.

[0003]

However, sugar infusion solution, amino acid infusion solution, electrolyte infusion solution and fat emulsion have different conditions under which they can exist stably, and when these are mixed, various problems occur and they cannot be used as an infusion solution. For example, a fat emulsion is an unstable formulation, and when mixed with other infusion solution, coarsening of oil and fat particles and phase separation (creaming) are likely to occur. In particular, the divalent metal ion contained in the electrolyte infusion causes aggregation of the fat emulsion and particle disintegration. Further, the electrolyte infusion contains calcium and phosphoric acid which are components necessary for maintaining the electrolyte balance, but phosphoric acid reacts with calcium to form calcium phosphate,
Turbidity and precipitation are likely to occur. In order to prevent the formation of turbidity and precipitate, the electrolyte infusion solution is usually adjusted to a low pH (less than pH 5). When this electrolyte infusion and amino acid infusion are mixed, the strong buffering action of the amino acid causes pH on the amino acid side.
Is controlled, and a large amount of acid agent (for example, hydrochloric acid, acetic acid, etc.) is required to lower the pH of the infusion solution. However, since the use of a large amount of acid agent impairs the balance of infusion components, there is a limit to the amount of acid agent that can be used and it is not possible to make the infusion solution have a low pH. During sterilization, turbidity and precipitation easily occur. Furthermore, it is known that when an amino acid infusion solution and a sugar infusion solution are mixed and sterilized by heating, remarkable coloring occurs due to the Maillard reaction.

As described above, when various infusions are mixed, various problems such as precipitation, deterioration, and coloring occur, so that sugar,
It is difficult to prepare and store an infusion solution containing an amino acid, an electrolyte and a fat emulsion in advance. Therefore, conventionally, a fat emulsion, a sugar infusion solution, an amino acid infusion solution and an electrolyte infusion solution are mixed and used at the time of use, and a stable infusion formulation containing a sugar, an amino acid, an electrolyte and a fat emulsion is desired. In view of the above circumstances, the present inventors have diligently studied a method for preparing a stable infusion formulation containing sugar, amino acid, electrolyte, and fat emulsion, and as a result, devised a combination of infusions containing these components, thereby providing excellent storage stability. At the same time, it was found that an infusion solution containing sugar, amino acid, electrolyte and fat emulsion can be easily obtained at the time of use, and various problems such as precipitation formation, alteration and coloring can be solved. That is, a container in which two separate chambers are formed by the isolation means is used, the first chamber contains an infusion solution containing a fat emulsion and sugar, and the second chamber contains an infusion solution containing an amino acid and an electrolyte. Sterilize and store in the state,
It has been clarified that the above problem can be solved by removing the isolation means at the time of use and mixing the infusion liquids in the first chamber and the second chamber (see JP-A-5-31151).

By the way, it has been common knowledge that various vitamins are used in combination in the high calorie infusion therapy, and various vitamins are added to the high calorie infusion for clinical use. Therefore, even in the infusion solution containing the newly developed sugar, amino acid, electrolyte and fat emulsion, the labor of adding vitamins at the time of clinical application is omitted, and in order to provide a complete high-calorie infusion solution, It is necessary to develop a high calorie infusion preparation containing vitamins in advance. However, vitamins are generally unstable, and when combined with certain vitamins, they cause decomposition and cloudiness of the liquid. For example, we have found that vitamin C is vitamin B ₁₂
It has been found that it promotes the decomposition of lactic acid, and that it is necessary to pay sufficient attention to the combination of vitamins. Also, there are water-soluble and fat-soluble vitamins, and there is a big difference in physicochemical properties between the two.
In particular, many water-soluble vitamins are unstable in solution.
Therefore, the present inventors have made various studies on the blending of vitamins, that is, the blending of the vitamins to be added to the first chamber (fat + sugar) and the second chamber (amino acid + electrolyte), Already filed a patent application. As a result of further diligent studies, the present inventors have found that by adding specific vitamins to the first and second chambers, the stability of sugars, amino acids, electrolytes and fat emulsions is not affected and We have succeeded in preparing an infusion formulation with further improved stability and completed the present invention.

[0006]

The container for infusion of the present invention made to solve the above-mentioned problems is a container in which two individual chambers are formed by a separating means, and a fat emulsion and sugar are provided in the first chamber. , Vitamin B ₁ , vitamin B ₂ , vitamin B ₁₂ , vitamin A, vitamin D, vitamin E and vitamin K are contained in the infusion solution, and the second chamber contains amino acids, electrolytes, vitamin C and folic acid. Infusion solution is stored. By adopting such a configuration, the isolation means is removed at the time of use, the first chamber and the second chamber are communicated with each other, and the infusion liquid contained in the first chamber and the infusion liquid contained in the second chamber are mixed. According to the fat emulsion, sugar,
An infusion solution containing amino acids, electrolytes and vitamins can be prepared. The average particle size of the fat emulsion contained in the first chamber is preferably 0.17 μm or less, and the infusion solution contained in the second chamber is a polyhydric alcohol or a phosphate ester of sugar as a phosphorus source. It is preferable to add the salt. Further, the infusion preparation of the present invention is an infusion preparation contained in each of the first chamber and the second chamber of the above-mentioned infusion container, and an infusion preparation obtained by removing the isolation means of the above-mentioned infusion container.

In the present invention having the above structure, the first
In the chamber there is a fat emulsion and sugar and at least vitamin B ₁ ,
An infusion solution containing vitamin B ₂ , vitamin B ₁₂ , vitamin A, vitamin D, vitamin E and vitamin K is contained. In the following description, for example, vitamin B
Vitamin (B ₁ , B ₂ ) when representing ₁ and vitamin B ₂
It is written as. As the fat emulsion, an oil-in-water emulsion prepared by dispersing fats and oils in water using an emulsifier is used. The fat emulsion can be prepared according to a conventional method,
For example, it can be carried out by adding an oil and fat and an emulsifier to water, stirring the mixture to prepare a crude emulsion, and then emulsifying the crude emulsion by a conventional method such as a high pressure emulsification method. As the above-mentioned oil and fat, any oil and fat can be used as long as it is an edible oil, for example, vegetable oil (for example, soybean oil, cottonseed oil, safflower oil, corn oil, coconut oil, perilla oil, perilla oil, etc.), fish oil (for example, Cod liver oil etc.), medium chain fatty acid triglycerides [eg Panacet (trade name), ODO (trade name) etc.] and chemically synthesized triglycerides [eg 2-linoleoyl-1,3-dioctanoylglycerol (8L8), 2 -
1 selected from chemically defined triglycerides such as linoleoyl-1,3-didecanoylglycerol (10L10)
One kind or two or more kinds of fats and oils are preferably used. Further, as the emulsifier, any emulsifier can be used as long as it is an emulsifier used in pharmaceutical formulations, for example, egg yolk phospholipids,
1 selected from hydrogenated egg yolk phospholipids, soybean phospholipids, hydrogenated soybean phospholipids and nonionic surfactants [eg Pluronic F68, HCO-60 (all are trade names), etc.]
One kind or two or more kinds of emulsifiers are preferably used. Particularly preferred is a fat emulsion using soybean oil as an oil and fat and egg yolk phospholipid as an emulsifier.

In the present invention, the average particle size of the fat emulsion is
It is preferably adjusted to 0.17 μm or less. With this particle size, conventional fat emulsion (average particle size 0.2-0.3μ
Compared with m), the stability is enhanced, and especially the phase separation of the fat emulsion due to the difference in specific gravity can be effectively suppressed. A fat emulsion having an average particle size of 0.17 μm or less can be obtained by adding one or two kinds selected from glycerin and glucose during the preparation of the fat emulsion and emulsifying. Conventionally, for the preparation of a fat emulsion, a method of adding a fat and oil and an emulsifier to water, stirring to prepare a coarse emulsion, and then emulsifying the coarse emulsion by a high pressure emulsification method or the like is used. According to the method, it is difficult to easily obtain an emulsion having an average grain size of 0.2 μm or less. However, the inventors have found that glycerin and glucose have a specific action of promoting micronization, and according to the above production method, a fat emulsion having an average particle size of 0.17 μm or less can be easily prepared. be able to.

In order to describe the method for producing the above fat emulsion more specifically, one example thereof is to add oil and fat and an emulsifier to water, and also to add 1 or 2 kinds selected from glycerin and glucose, and then stir. To prepare a crude emulsion, and then the crude emulsion is emulsified by a conventional method such as a high pressure emulsification method to prepare a fat emulsion. When the above emulsification is performed by a high-pressure emulsification method, for example, using an emulsifying machine such as Manton-Gaulin homogenizer, the crude emulsion is 20 ~ 700K
It is carried out by passing it 5 to 50 times under the condition of g / cm ² . In this method, glycerin and /
Or glucose may be present when emulsifying, for example,
Glycerin and / or was added to the crude emulsion prepared with oil and fat and emulsifier.
Alternatively, glucose may be added to emulsify. In addition,
The average grain size of the obtained emulsion can be measured by using a conventional measuring method such as a light scattering method.

In the above-mentioned production method, the amount of fats and oils, emulsifiers and glycerin and / or glucose used is 0.1 to 30 W / V% of fats and oils (hereinafter, unless otherwise specified,% is W / V%)), preferably 1 to 20%, an emulsifier 0.01 to 10%, preferably 0.05 to 5%,
Glycerin and / or glucose are used in an amount adjusted to about 30 to 70%, preferably about 40 to 60% and an appropriate amount of water.

As the sugar contained in the infusion solution contained in the first chamber, various sugars can be blended, but reducing sugar is preferably used. Examples of the reducing sugar include glucose, fructose, maltose, and the like, and these reducing sugars may be used as a mixture of two or more kinds. Further, a mixture obtained by adding sorbitol, xylitol, glycerin or the like to these reducing sugars may be used.

The first chamber contains at least vitamins (B ₁ , B ₂ , B ₁₂ , A, D, E, K) as vitamins. Such vitamins may be derivatives, and specifically, as vitamin B ₁ , thiamine hydrochloride, prosultiamine, octothiamine, etc., and as vitamin B ₂ , riboflavin phosphate, flavin mononucleotide, flavin adenine dinucleotide, etc. However, as vitamin B ₁₂ , cyanocobalamin, hydroxocobalamin acetate, methylcobalamin, etc., as vitamin A, retinol palmitate, etc., as vitamin D, cholecalciferol (D ₃ ), ergocalciferol (D ₂ ), etc., Examples of vitamin E include dl-α-tocopherol and tocopherol acetate, and examples of vitamin K include phytonadione, menatetrenone and menadione.

The infusion solution contained in the first chamber can be prepared by various methods. For example, sugar may be added to the fat emulsion prepared by the above method. You may add it. Vitamins (B ₁ ,
As a method for adding B ₂ , B ₁₂ , A, D, E, K), the fat-soluble vitamin [vitamin (A, D, E, K)] may be dissolved in the oil or fat in advance. In addition, vitamins (B ₁ , B ₂ ,
B ₁₂₎ after preparation of the emulsion, it is sufficient to dissolve to the water for injection at a liquid amount adjustment in the water for injection. The composition of the fat emulsion, sugar and vitamin in the first chamber is determined by the concentration of the infusion solution (that is, the infusion solution containing amino acid, electrolyte and vitamin) contained in the second chamber, the infusion solution contained in the first and second chambers. It can be appropriately adjusted depending on the volume ratio of
About 0.1 to 30%, preferably about 1 to 20%, more preferably
2-10%, emulsifier 0.01-10%, preferably 0.05-5
%, More preferably about 0.1 to 2%, sugar 5 to 60%, preferably about 7 to 40%, more preferably about 10 to 30%, vitamin B _{1 1 to} 30 mg / l, preferably 1.5 to 23 mg / l, more preferably about 2 to 15 mg / l approximately, vitamin B ₂ 1 to 20
mg / l, preferably 1.5 to 15 mg / l, more preferably 2 to 10 mg / l, vitamin B ₁₂ 1 to 50 μg / l, preferably 2 to 30 μg / l, more preferably 4 to 20 μg / l. l, vitamin A 1000-8000 IU / l, preferably 2000
~ 7500 IU / l, more preferably 3000-7000 IU / l, vitamin D 100-1500 IU / l, preferably 125-
1000 IU / l, more preferably 150-800 IU / l, vitamin E 5-60 mg / l, preferably 6-40 mg / l,
More preferably about 7 to 30 mg / l, vitamin K 0.2 to 10 mg /
l, preferably 0.5 to 7.5 mg / l, more preferably 1
An infusion solution consisting of about 5 mg / l and an appropriate amount of water is exemplified.

The second chamber contains an infusion solution containing an amino acid, an electrolyte, and at least vitamin C (ascorbic acid) and folic acid. Examples of amino acids include various amino acids (essential amino acids, non-essential amino acids) that have been conventionally contained in amino acid infusions for the purpose of nutritional supplementation to the living body. For example, L-isoleucine, L-leucine,
L-valine, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, L
-Arginine, L-histidine, glycine, L-alanine, L-proline, L-aspartic acid, L-serine,
L-tyrosine, L-glutamic acid, L-cysteine and the like are exemplified. These amino acids are not necessarily used in the form of free amino acids, and include inorganic acid salts (for example, L-lysine hydrochloride, etc.), organic acid salts (for example, L-lysine acetate, L-lysine malate, etc.). ), An in vivo hydrolysable ester form (for example, L-tyrosine methyl ester, L-methionine methyl ester, L-methionine ethyl ester, etc.), N-substituted form (for example, N-acetyl-L-tryptophan, N -Acetyl-L-cysteine, N-acetyl-L-proline, etc.), dipeptides having the same or different amino acids as peptide bonds (for example, L-tyrosyl-L-tyrosine, L-alanyl-L-).
Tyrosine, L-arginyl-L-tyrosine, L-tyrosyl-L-arginine, etc.) and the like.

Examples of the electrolyte include various water-soluble salts conventionally used for infusion, and for example, various inorganic components (eg, various inorganic components required for maintaining the function of a living body and the electrolyte balance of body fluid). Examples thereof include water-soluble salts of sodium, potassium, calcium, magnesium, zinc, iron, copper, manganese, iodine, phosphorus and the like (for example, chloride, sulfate, acetate, gluconate, lactate, etc.). A hydrate may be added to these water-soluble salts.

In the above electrolyte component, a polyhydric alcohol or a phosphoric acid ester of sugar or a salt thereof is preferably used as a source of phosphorus. As the phosphate ester of polyhydric alcohol, glycerophosphate, mannitol-1-
Examples thereof include phosphoric acid and sorbitol-1-phosphoric acid. Further, examples of the phosphoric acid ester of sugar include glucose-6-phosphoric acid, fructose-6-phosphoric acid, and mannose-6-phosphoric acid. As the salts of these phosphoric acid esters, alkali metal salts such as sodium salts and potassium salts are preferably used. As a preferred phosphate salt,
The sodium salt or potassium salt of glycerophosphoric acid may be mentioned.

Preferred examples of the electrolyte component include the following compounds. Sodium: sodium chloride, sodium lactate, sodium acetate, sodium sulfate, sodium glycerophosphate potassium: potassium chloride, potassium glycerophosphate, potassium sulfate, potassium acetate, potassium lactate calcium: calcium gluconate, calcium chloride,
Calcium glycerophosphate, calcium lactate, calcium pantothenate, calcium acetate magnesium: magnesium sulfate, magnesium chloride,
Magnesium glycerophosphate, magnesium acetate, magnesium lactate Phosphorus: Potassium glycerophosphate, sodium glycerophosphate, magnesium glycerophosphate, calcium glycerophosphate Zinc: zinc sulfate, zinc chloride, zinc gluconate, zinc lactate, zinc acetate

The second chamber contains at least vitamin C and folic acid as vitamins. Such a vitamin may be a derivative, and specific examples of vitamin C include ascorbic acid, sodium ascorbate, and magnesium phosphate ascorbate.

The infusion solution contained in the second chamber can be prepared by various methods. For example, it is prepared by dissolving various amino acids and electrolytes to be mixed in purified water such as water for injection. As a method for adding vitamin C and folic acid, it may be added and dissolved together with the dissolution of the amino acid and the electrolyte. The composition of amino acids, electrolytes and vitamins in the second chamber depends on the concentration of the infusion solution (that is, the infusion solution containing fat emulsion, sugar and vitamin) contained in the first chamber, and the infusion solution to be infused into the first and second chambers. Although it can be appropriately adjusted by the volume ratio and the like, for example, the total amount of amino acids is about 1 to 15%, preferably about 2 to 13%, more preferably about 3 to 12%, as an electrolyte, sodium 50 to 180 mEq / l, Potassium 40 ~
135mEq / l, Calcium 10-50mEq / l, Magnesium 5-30mEq / l, Chlorine 0-225mEq / l, Phosphorus 3-40
mEq / l, zinc 0-100μmol / l, vitamin C 50-5
00 mg / l, preferably 75 to 400 mg / l, more preferably 100 to 350 mg / l, folic acid 0.1 to 2 mg / l, preferably 0.3 to 1.8 mg / l, more preferably 0.5 to 1.5 mg / l. An infusion solution consisting of about l and an appropriate amount of water is exemplified.

Other vitamins such as vitamin B ₆ (eg pyridoxine hydrochloride, pyridoxal phosphate, pyridoxamine phosphate etc.), nicotinic acids (eg nicotinic acid, nicotinic acid amide etc.), pantothenic acids (eg
Sodium pantothenate, calcium pantothenate, pantothenol, etc.) and biotin may be added to either the first chamber, the second chamber, or both chambers.
Also, these vitamins may be added as derivatives. When it is added to the first chamber, it may be prepared at the same time as the vitamins (B ₁ , B ₂ , B ₁₂ ) are dissolved. Further, when it is added to the second chamber, it may be performed together with the dissolution of vitamin C and folic acid. In a specifically preferred embodiment, vitamin B ₆ is contained in the second chamber at about 1 to 20 mg / l, preferably
It is blended at a ratio of about 3 to 19 mg / l, more preferably about 5 to 18 mg / l. Nicotinic acid in the first chamber is about 10-200 mg / l,
Preferably about 20-180 mg / l, more preferably 30-150 mg
Mix at a ratio of about 1 / l. Pantothenic acids 5 in room 1
The amount is about 80 mg / l, preferably about 7 to 70 mg / l, and more preferably about 10 to 60 mg / l. Biotin is second
20 ~ 600μg / l in the chamber, preferably about 30 ~ 500μg / l,
More preferably, it is blended at a rate of about 40 to 400 μg / l.

The amount of the infusion solution contained in the first and second chambers, and the types, mixing ratios and concentrations of the fat emulsion, sugar, amino acid, electrolyte and vitamin of each infusion solution, use, disease of the patient to be administered, symptoms, etc. Can be appropriately adjusted according to the above, but preferably each component of the first chamber and the second chamber
And the concentrations described in 3 and 3, if necessary, vitamin B ₆ , pantothenic acids, nicotinic acids and / or biotin are added to the first chamber and / or the second chamber, and the first chamber and the second chamber are added. The liquid volume ratio of 1: 1 to 5: 1, preferably 2.
Filling the container to 5: 1 to 3.5: 1
This is preferable from the viewpoint of well-balanced administration of the required amount of each component to humans and the stability of the preparation. Therefore, the infusion preparation of the present invention prepared by mixing the infusion solutions contained in the first chamber and the second chamber is preferably adjusted so that each component has the following concentration range. Fats and oils 5 to 50 g / l Emulsifiers 0.5 to 10 〃 Sugars 50 to 250 〃 L-isoleucine 0.5 to 5 〃 L-leucine 0.5 to 7 〃 L-valine 0.5 to 5 〃 L-lysine 0 .5 to 7 〃 L-methionine 0.1 to 4 〃 L-phenylalanine 0.3 to 5 〃 L-threonine 0.3 to 5 〃 L-tryptophan 0.1 to 1 〃 L-arginine 0.3 to 7 〃 L-histidine 0.2 to 3 〃 glycine 0.2 to 3 〃 L-alanine 0.3 to 5 〃 L-proline 0.2 to 5 〃 L-aspartic acid 0.03 to 2 〃 L-serine 0.2 ~ 3〃L-tyrosine 0.03 to 0.5〃L-glutamic acid 0.03 to 2〃L-cysteine 0.03 to 1〃sodium 15 to 60 mEq / l potassium 10 to 50〃calcium 3 to 5 〃 Magnesium 2-10 〃 chlorine 0-80 〃 phosphorus 1-15 〃 zinc 0 ~ 30 μmol / l vitamin B ₁ 0.5 ~ 20 mg / l vitamin B ₂ 0.5 ~ 10 〃 vitamin B ₁₂ 0.5 〜 20 μg / l Vitamin A 500 〜 6000 IU / l Vitamin D 50 〜 600 〃 Vitamin E 3 〜 20 mg / l Vitamin K 0.1 〜 5 〃 Vitamin C 20 〜 200 〃 Folic acid 0.05 〜 1 〃 Vitamin B ₆ 0.5 to 10 〃 Pantothenic acids 1 to 30 〃 Biotin 10 to 200 µg / l Nicotinic acids 5 to 100 mg / l

The fluidity of the infusion solution contained in the first chamber and the second chamber is not particularly limited, but p is preferable from the viewpoint of safety for the living body.
H should be adjusted to 5.0 to 8.0, preferably 5.5 to 7.0. In particular, when a polyhydric alcohol or a phosphoric acid ester of sugar or a salt thereof is used as a phosphorus supply source in the infusion solution contained in the second chamber, the precipitation is effectively suppressed even at a relatively high pH. be able to. The pH adjuster used for adjusting the pH of each of the above infusions is not particularly limited as long as it is physiologically acceptable, and various acid agents can be used, but organic acids are preferably used. As an organic acid,
For example, citric acid, gluconic acid, lactic acid, malic acid, maleic acid, malonic acid and the like can be mentioned. In particular, an organic acid having a chelating power for a divalent metal ion is preferable, and citric acid is preferably used.

In addition, an anti-coloring agent (for example, thioglycerol, dithiothreitol, etc.) is added to the infusion solutions contained in the first and second chambers to prevent coloring during sterilization and storage. Also, the addition amount of the anti-coloring agent is usually
It is about 1% or less. The anti-coloring agent may be added to the infusion solution in the first chamber, the infusion solution in the second chamber, or both. Further, a buffer such as L-histidine, tris (hydroxymethyl) aminomethane or the like may be added to the infusion solution contained in the first chamber, and the addition amount of these is usually about 1% or less. . The infusion solution contained in the second chamber contains thioglycerol, sodium bisulfite, and
You may add sodium sulfite etc. The addition amount of these is usually about 0.001% to 0.1%.

The infusion solution contained in the first and second chambers may be sterilized in advance by heat sterilization or the like and then aseptically filled and sealed in each chamber, but preferably the first and second chambers are used. Two
A method is used in which each chamber is filled with an infusion solution (preferably in the presence of an inert gas), sealed, and then sterilized.
Sterilization can be carried out according to a conventional method, for example, a heat sterilization method such as high-pressure steam sterilization, hot water immersion sterilization, hot water shower sterilization and the like.

Examples of the container used in the present invention include a glass container, a plastic (for example, polypropylene, polyethylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, polyamide, polyester, etc.) container. In particular, a flexible container made of a plastic film or sheet is preferably used, and as the material for the plastic film and sheet, the above-mentioned materials and their laminated bodies are used. Further, as the container, a container made of a material that can withstand heat sterilization is preferable. Further, in consideration of stability during storage, the container preferably has a light-shielding property, and examples thereof include a light-shielding bag and an ultraviolet ray shielding container.

[0026]

The present invention will be described in more detail with reference to the drawings showing examples, but the present invention is not limited to these examples. FIG. 1 is a schematic view showing one embodiment of a container containing an infusion solution of the present invention. In the figure, the container 1 is made of a material such as a plastic film (including a sheet, the same applies hereinafter), and has two individual chambers, a first chamber 2 and a second chamber 3. In the first chamber 2, a fat emulsion and sugar and vitamins (B ₁ , B ₂ , B ₁₂ , A, D, E, K) (hereinafter referred to as the first
The infusion solution 4 containing the room vitamins is contained, and the second chamber 3 contains the infusion solution 5 containing the amino acid and the electrolyte and vitamin C and folic acid (hereinafter referred to as the second room vitamins). However, the first chamber 2 and the second chamber 3 are connected to the communication portion 6 that communicates them so that the infusion solution 4 contained in the first chamber 2 and the infusion solution 5 contained in the second chamber 3 are not mixed. It is isolated by an isolation means such as a pinch cock 7 provided. Further, in the container 1, the infusion solution 4 is placed in the first chamber 2.
A port 8 for injecting the infusion solution, a port 9 for injecting the infusion solution 5 into the second chamber 3, and a port 10 for taking out the infusion solution after mixing are provided. If necessary, other agents can be injected through these ports.

The above-mentioned infusion solution-containing container is obtained as follows. First, the communication part 6 of the container 1 is shut off by an isolation means such as a pinch cock 7 to isolate the first chamber 2 and the second chamber 3,
Then, an infusion solution containing a fat emulsion, sugar, and first-chamber vitamins is injected into the first chamber 2 through the port 8, and an infusion solution containing an amino acid, an electrolyte, and a second-chamber vitamin through the port 9. Is injected into the second chamber 3. At this time, the first chamber 2
And / or vitamin B ₆ , nicotinic acids, pantothenic acids, and biotin may be added to the infusion solution contained in the second chamber 3 if necessary. The infusion liquids 4 and 5 are preferably injected into the first chamber 2 and the second chamber 3 under a stream of an inert gas (eg, nitrogen gas, argon gas, etc.). After the injection of the infusion solutions 4 and 5 into the first chamber 2 and the second chamber 3 is completed, the ports 8 and 9 are sealed and then sterilized to obtain the infusion solution-containing container shown in FIG. 1. The sterilization can be performed according to a conventional method, for example, a heat sterilization method such as high-pressure steam sterilization, hot water immersion sterilization, hot water shower sterilization, etc., and a plastic container is used as in this example. In some cases, it is preferable to sterilize in an atmosphere containing substantially no oxygen. The container with an infusion solution of the present invention thus obtained can be stored in that state, and the pinch cock 7 is removed at the time of use to make the first chamber 2 and the second chamber 3 communicate with each other, and the infusion solution 4 contained in each container. By mixing 5 and 5, an infusion solution containing a fat emulsion, sugar, amino acid, electrolyte and vitamin can be prepared aseptically. Then, the above mixed infusion is aseptically taken out from the port 8 through a tube (not shown) and administered to a living body.

FIG. 2 is a schematic view showing another embodiment of the infusion container of the present invention. In the figure, the container 11 is made of a material such as a plastic film, and is isolated by a large screw cock 16 to separate the first chamber 12 and the second chamber.
Two private chambers, chamber 13 are formed. Infusion fluid 14 containing fat emulsion, sugar and vitamins in the first compartment 12
Is contained in the second chamber 13, and an infusion solution 15 containing an amino acid, an electrolyte and vitamins in the second chamber is contained in the second chamber 13, but the first chamber 12 and the second chamber 13 are isolated by the screw cock 16 described above. Infusion solution 14 contained in the first chamber 12 and infusion solution 1 contained in the second chamber 13
5 never mix. Further, the container 11 has a port 17 for injecting the infusion solution 14 into the first chamber 12, and the second chamber 1
3 is provided with a port 18 for injecting the infusion solution 15 and a port 19 for taking out the infusion solution after mixing.
If necessary, other agents can be injected through these ports. The method of manufacturing and using the infusion solution-containing container shown in FIG. 2 is substantially the same as those of the infusion solution-containing container shown in FIG.

FIG. 3 is a schematic view showing another embodiment of the container containing the infusion solution of the present invention. In the same figure, the container 21 is made of a material such as a plastic film, and is separated by a partition band portion 28 formed by heat-sealing the film forming the container, so that the first chamber 22 and the second chamber 23 are separated from each other. Two private rooms are formed. The partition strip 28 is formed so as to be peelable by applying an external force. The first chamber 22 contains an infusion solution 24 containing a fat emulsion, sugar and the first chamber vitamins, and the second chamber 23 contains an infusion solution 25 containing an amino acid, an electrolyte and a second chamber vitamins. However, since the first chamber 22 and the second chamber 23 are separated by the partition section 28, the infusion solution 2 contained in the first chamber 22
4 does not mix with the infusion solution 25 contained in the second chamber 23. In addition, the container 21 has an infusion solution 24 in the first chamber 22.
Infusion 2 in port 26 for injecting and second chamber 23
A port 27 for injecting 5 is provided. If necessary, other agents can be injected through these ports. The port 26 or 27 is used to take out the infusion solution.
The infusion solution-containing container shown in FIG.
It is manufactured by filling one of the first chamber 22 and the second chamber 23, which is isolated in step 1, with an infusion solution, sealing it, inverting it, and filling the other chamber with the infusion solution. The sterilization method and the use method are substantially the same as those of the infusion container shown in FIG.
In this container, an external force is applied at the time of use and the partition strip 2
8 is peeled off and opened to open the first chamber 22 and the second chamber.
The infusion solutions contained in chamber 23 are mixed.

The infusion solution containing container shown in FIGS. 1, 2 and 3 is one embodiment of the present invention, and is not limited thereto. The shape, size, etc. of the container can be changed as appropriate, and a suspending portion for locking the infusion-containing container with a conventional suspending tool may be provided at an appropriate position on the container body. Further, the isolation means is not limited to the above example, and for example, in FIG. 1, a clip or the like may be used instead of the pinch cock 7, and a ball stopper is provided in the communication part 6 to provide the first chamber. 2 and the second chamber 3 may be separated.

The container containing the infusion solution of the present invention may be packaged with an oxygen impermeable membrane material in order to prevent alteration of the infusion solution in the container. As the oxygen impermeable membrane material, for example, a three-layer laminate film including an ethylene-vinyl alcohol copolymer film, a polyvinyl alcohol film, a polyvinylidene chloride film or the like as an intermediate layer (for example, the outer layer is a polyester film, a stretched nylon film). , A laminated film made of a stretched polypropylene film or the like, and an inner layer made of an unstretched polypropylene film),
Laminated film containing an aluminum layer (for example, polyester film-aluminum layer-laminated film composed of unstretched polypropylene film), laminated film containing an inorganic vapor deposition film (eg polyester film-silicon deposited film-unstretched polypropylene film, stretched nylon) Film-silicon vapor deposition film-unstretched polypropylene film, polyester film-aluminum vapor deposition film-unstretched polypropylene film, alumina vapor deposition polyester film-polyvinylidene chloride film-laminated film comprising unstretched polypropylene film, etc.). Further, an oxygen absorber (eg, Ageless, trade name) may be contained between the outer packaging and the container, and further vacuum packaging, inert gas (eg nitrogen gas, etc.) filling packaging may be performed according to a conventional method. It is also possible to

The infusion solution containing a fat emulsion, sugar, amino acid, electrolyte and vitamin, which is obtained by mixing the infusion solutions contained in the first and second chambers, has good storability and precipitate formation,
It can be stored without causing alteration or coloring.
The infusion solution is intravenously administered to a patient as it is or after diluting it with water, or alone or in combination with a drug or the like as necessary. Furthermore, it can be used for administration in a dosage form such as oral administration and enteral administration.

Hereinafter, the present invention will be described in more detail based on production examples.
However, the present invention is not limited to these examples.
There is no. Production example 1(1) Preparation of infusion solution containing fat emulsion, sugar and vitamins  Vitamin A Palmitate 12000IU, Vitamin D₃
1200 IU, Vitamin E (α-tocopherol) 45
mg and vitamin K₁6 mg was dissolved in 66 g of soybean oil
9.5g egg yolk phospholipids and 500g glucose
Add to water and homogenize with a homomixer, then
(B₁) 15 mg, riboflavin phosphate (B₂) 15m
g, cyanocobalamin (B₁₂) 30 μg, pantotheno
45 mg and 120 mg nicotinamide were dissolved.
Add water and adjust the total volume to 1000 ml.
Got The crude emulsified liquid thus obtained was treated with Manton-Gorin homogenate.
Average particle size with a Nizer (15M-8TA, manufactured by Gorin Co., Ltd.)
To 0.17 μm or less to obtain an emulsion. Profit
Add water to the prepared emulsion (500 ml) to bring the total volume to 1000 ml.
And The composition of the obtained infusion solution is shown in Table 1.

[0034]

[Table 1]

(2) Contains amino acids, electrolytes and vitamins
Preparation of Infusion Solution Having Amino acids, electrolytes and vitamins shown in Table 2, Table 3 and Table 4 are added and dissolved in water for injection heated to about 80 ° C. under a nitrogen stream to obtain citric acid. Was used to adjust the pH to 6.2.

[0036]

[Table 2]

[0037]

[Table 3]

[0038]

[Table 4]

(3) Preparation of Infusion-Containing Container A polyethylene container having the shape shown in FIG. 3 was used. The first compartment 22 of the container 21 in which the first compartment 22 and the second compartment 23 are formed by fusing the partition strip 28 in a peelable manner contains the fat emulsion, sugar and vitamin obtained in (1) above. 600 ml of the infusion solution was injected from the port 26 while being filled with nitrogen gas, and the port 26 was sealed after the injection. Then, the container 21 is inverted, and the infusion solution 300 containing the amino acid, the electrolyte and the vitamin obtained above is placed in the second chamber 23.
Injecting ml from port 27 while filling with nitrogen gas,
After the injection, the port 27 was sealed. Container 1 containing each infusion
Was subjected to high-pressure steam sterilization (115 ° C., 30 minutes) and then cooled to room temperature to obtain an infusion container of the present invention.

(4) Prepared using the container containing the infusion solution of the present invention
Stability test of the infused fluid The partition strip 28 of the infusion solution-containing container obtained in (3) above was peeled off, and the infusion fluid in the first chamber 22 and the infusion fluid in the second chamber 23 were thoroughly mixed to obtain a fat emulsion. An infusion solution containing sugar, amino acid, electrolyte and vitamins was obtained. The composition of the thus prepared infusion solution is shown in Table 5. The infusion solution obtained above was stored at 25 ° C. for 1 week, and during that period, changes in appearance, average particle size of fat emulsion and turbidity were measured. Table 6 shows the results. As a control, an infusion solution prepared by injecting 300 ml of water for injection into the second chamber 23 and similarly sterilized was used. The average particle size of the fat emulsion was measured by a light scattering method and the turbidity was 620 nm (1 c
It was measured by the absorbance of m cell). As shown in Table 6, no changes in appearance, particle size and turbidity were observed, and it was revealed that the infusion solution prepared using the infusion solution-containing container of the present invention has high stability.

[0041]

[Table 5]

[0042]

[Table 6]

Experimental Example 1 (1) Method The relationship between the vitamin composition of each room and the stability of the infusion preparation was investigated. According to the compositions shown in Comparative Example 1 and Comparative Example 2 in Table 7 and the column of the present invention, an infusion liquid for the first chamber and an infusion liquid for the second chamber were respectively prepared. Each of the infusion solutions prepared above was filled in a polyethylene container and subjected to high-pressure steam sterilization (under nitrogen gas load) at 115 ° C. for 15 minutes. After cooling to room temperature, the container is placed in an oxygen-impermeable packaging container together with an oxygen scavenger,
It was stored at 7 ° C for 7 days, and the residual rate (%) of various vitamins was examined. The results are shown in Table 8. The residual rate was determined by a known vitamin quantitative analysis method as a ratio after storage to immediately after sterilization.

[0044]

[Table 7]

[0045]

[Table 8]

(2) Results As shown in Comparative Example 1 of Table 8, Na ascorbate
When (C) and folic acid were added to the first compartment (fat + sugar), the residual rate decreased, whereas when added to the second compartment (amino acid + electrolyte), a high residual rate was exhibited. On the other hand, it was found that thiamine nitrate (B ₁ ) and riboflavin phosphate (B ₂ ) had a higher residual rate in the first chamber than in the second chamber. In addition, pyridoxine hydrochloride (B ₆ )
A high residual rate was exhibited when it was added to both the chamber and the second chamber, and it was revealed that it can be added to both of the chambers. In addition,
Regarding biotin and pantothenic acid, it has been confirmed from a separately conducted test that a high residual rate can be obtained regardless of whether they are added to the first chamber or the second chamber. Further, as shown in Comparative Example 2 in Table 8, it was revealed that cyanocobalamin (B ₁₂ ) hardly remains when it is added to the second chamber, whereas the residual rate increases when it is added to the first chamber. . It was revealed that nicotinic acid amide showed a high residual rate when added to both the first chamber and the second chamber, and could be added to both chambers. In contrast, in the formulation of the present invention,
It was shown that various vitamins were held in a stable and well-balanced manner, and had extremely good storage stability. in this way,
It is noteworthy that the composition of vitamins was modified to find a composition with good stability.

Experimental Example 2 The formulation of the present invention was stored at 25 ° C. for 60 days after sterilization, and the residual rate (%) of various vitamins was measured. The results are shown in Table 9. The sterilization method and the method of measuring the residual rate are the same as in Experimental Example 1. As shown in Table 9,
It was found that the preparation of the present invention has a high residual rate of vitamins and has good storage stability.

[0048]

[Table 9]

[0049]

As described above, in the present invention, the two isolated chambers are pre-filled with the infusion solution containing the fat emulsion, sugar and vitamin, and the infusion solution containing the amino acid, electrolyte and vitamin. An infusion solution containing sugar, amino acids, electrolytes, fat emulsions and vitamins can be prepared by simply removing the isolation means at the time of use, and even though the infusion solution thus obtained contains each of these components, it precipitates. It shows high stability without causing phase separation or alteration. Therefore, according to the present invention, an infusion solution having excellent stability and safety can be obtained, and further, a fat emulsion,
Since the operation of mixing sugar, amino acid, electrolyte and vitamin is not required, the operation is simplified and the effect of preventing bacterial contamination during mixing can be obtained. In particular, study the combination of vitamins, that is, the combination of vitamins to be added to the first chamber (fat + sugar) and the second chamber (amino acid + electrolyte), and further devise the addition means. As a result, it was possible to prepare an infusion preparation having good stability of vitamins without affecting the stability of sugar, amino acid, electrolyte and fat emulsion. Therefore, sugar
With regard to an infusion solution containing an amino acid / electrolyte and a fat emulsion, it has become possible to provide a complete high-calorie infusion preparation without the need to add vitamins during clinical application.

[Brief description of drawings]

FIG. 1 is a schematic view showing an embodiment of a container containing an infusion solution of the present invention.

FIG. 2 is a schematic view showing another embodiment of the infusion solution-containing container of the present invention.

FIG. 3 is a schematic view showing another embodiment of the infusion solution container according to the present invention.

[Explanation of symbols]

1, 11, 21 Container 2, 12, 22 First chamber 3, 13, 23 Second chamber 4, 14, 24 Infusion solution containing fat emulsion, sugar and first chamber vitamins 5, 15, 25 Amino acid, electrolyte and Second chamber Infusion solution containing vitamins 6 Communication part 7, 16, 28 Isolation means 8, 9, 10, 17, 18, 19, 26, 27 Port

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location A61K 31/12 9455-4C 31/195 9455-4C 31/355 31/375 31/51 31/525 31/68 31/70 33/00 (72) Inventor Shigeo Ii 1-3-3 Imabashi, Chuo-ku, Osaka Midori Cross Co., Ltd. (72) Inventor Shunichi Abe 2-25-Otani, Hirakata, Osaka Prefecture No. 1 Incorporated company Midori Cross Central Research Institute (72) Inventor Kazumasa Yokoyama 1-3-3 Imabashi, Chuo-ku, Osaka City Midori Cross Inc.

Claims (10)

[Claims] 1. A container in which two individual chambers are formed by an isolation means, and the first chamber has a fat emulsion, sugar, and vitamin B.
Infusion fluid containing ₁ , Vitamin B ₂ , Vitamin B ₁₂ , Vitamin A, Vitamin D, Vitamin E and Vitamin K is stored in the second chamber, and infusion fluid containing Amino Acid, Electrolyte, Vitamin C and Folic Acid is stored. A container containing an infusion characterized in that 2. The infusion solution contained in the first chamber is oil / fat 0.1 to 30 (W / V)% emulsifier 0.01 to 10 〃 sugar 5 to 60 〃 vitamin B _{1 1 to} 30 mg / l vitamin B ₂ 1 to 20 〃 Vitamin B ₁₂ 1 to 50 µg / l Vitamin A 1000 to 8000 IU / l Vitamin D 100 to 1500 〃 Vitamin E 5 to 60 mg / l Vitamin K 0.2 to 10 〃 The container containing the infusion solution according to claim 1. 3. The infusion solution contained in the second chamber contains a total amount of amino acids 1 to 15 (W / V)% as an electrolyte sodium 50 to 180 mEq / l potassium 40 to 135 〃 calcium 10 to 50 〃 magnesium 5 to 30 The container with an infusion solution according to claim 1 or 2, which is an infusion solution containing 0 to 225 chlorine, 3 to 40 phosphorus, 0 to 100 μmol / l vitamin C, 50 to 500 mg / l folic acid, and 0.1 to 2 〃. 4. One or more components selected from vitamin B ₆ , pantothenic acids, nicotinic acids and biotin,
The infusion solution-containing container according to claim 1, which is contained in at least one of the first chamber and the second chamber. 5. An infusion preparation containing a fat emulsion, sugar, vitamin B ₁ , vitamin B ₂ , vitamin B ₁₂ , vitamin A, vitamin D, vitamin E and vitamin K. 6. oil 0.1~30 (W / V)% emulsifier 0.01-10 〃 sugar 5-60 〃 vitamin B ₁ 1~30 mg / l vitamin B ₂ 1 to 20 〃 vitamin B _12. 1 to The infusion preparation according to claim 5, which is an infusion containing 50 µg / l vitamin A 1000 to 8000 IU / l vitamin D 100 to 1500 〃 vitamin E 5 to 60 mg / l vitamin K 0.2 to 10 〃. 7. An infusion preparation containing an amino acid, an electrolyte, vitamin C and folic acid. 8. Amino acid total amount 1 to 15 (W / V)% as electrolyte sodium 50 to 180 mEq / l potassium 40 to 135 〃 calcium 10 to 50 〃 magnesium 5 to 30 〃 chlorine 0 to 225 〃 phosphorus 3 to 40 〃 The infusion preparation according to claim 7, which is an infusion containing zinc 0 to 100 µmol / l vitamin C 50 to 500 mg / l folic acid 0.1 to 2 〃. 9. A fat emulsion prepared by removing the isolation means of the container containing the infusion solution according to claim 1 and mixing the infusion solutions contained in the first chamber and the second chamber,
A comprehensive high-calorie infusion formulation containing vitamins containing sugar, amino acids, electrolytes and vitamins. 10. The infusion preparation according to claim 9, which contains the following components. Fats and oils 5 to 50 g / l Emulsifiers 0.5 to 10 〃 Sugars 50 to 250 〃 L-isoleucine 0.5 to 5 〃 L-leucine 0.5 to 7 〃 L-valine 0.5 to 5 〃 L-lysine 0 .5 to 7 〃 L-methionine 0.1 to 4 〃 L-phenylalanine 0.3 to 5 〃 L-threonine 0.3 to 5 〃 L-tryptophan 0.1 to 1 〃 L-arginine 0.3 to 7 〃 L-histidine 0.2 to 3 〃 glycine 0.2 to 3 〃 L-alanine 0.3 to 5 〃 L-proline 0.2 to 5 〃 L-aspartic acid 0.03 to 2 〃 L-serine 0.2 ~ 3〃L-tyrosine 0.03 to 0.5〃L-glutamic acid 0.03 to 2〃L-cysteine 0.03 to 1〃sodium 15 to 60 mEq / l potassium 10 to 50〃calcium 3 to 5 〃 Magnesium 2-10 〃 chlorine 0-80 〃 phosphorus 1-15 〃 zinc 0 ~ 30 μmol / l vitamin B ₁ 0.5 ~ 20 mg / l vitamin B ₂ 0.5 ~ 10 〃 vitamin B ₁₂ 0.5 〜 20 μg / l Vitamin A 500 〜 6000 IU / l Vitamin D 50 〜 600 〃 Vitamin E 3 〜 20 mg / l Vitamin K 0.1 〜 5 〃 Vitamin C 20 〜 200 〃 Folic acid 0.05 〜 1 〃 Vitamin B ₆ 0.5 to 10 〃 Pantothenic acids 1 to 30 〃 Biotin 10 to 200 µg / l Nicotinic acids 5 to 100 mg / l