JP4828111B2 - General infusion preparation - Google Patents

Description

  The present invention relates to a general infusion preparation containing amino acids, reducing sugars and vitamins. The present invention relates to a general infusion preparation containing trace metal elements and iodine in addition to the above components.

  A reducing sugar solution, an amino acid solution, and a vitamin solution are provided in a container having two chambers (A chamber and B chamber) separated by a partition wall that can communicate and a small container (C chamber) that can communicate with either one of the two chambers. Several cases that have been separated and accommodated have been studied.

For example, Patent Document 1 discloses an infusion solution containing amino acids and vitamin C in the A chamber, an infusion solution containing reducing sugar, vitamin B ₁ and vitamin B ₂ in the B chamber, vitamin A, vitamin D and vitamin E, and vitamins in the C chamber. There is disclosed a general infusion preparation which is filled with an infusion solution containing K, and in which an electrolyte is further contained in the infusion solution of the A chamber and / or the B chamber.

Patent Document 2 discloses an infusion solution containing amino acids, vitamin B ₂ and vitamin C in the A chamber, an infusion solution containing reducing sugar and vitamin B ₁ in the B chamber, vitamin A, vitamin D, vitamin E, vitamin K in the C chamber. and vitamin B ₁₂ and infusion containing is filled with a nutritional transfusion agent is disclosed further electrolyte infusion chamber a and / or B chamber is contained.

Patent Document 3 discloses an infusion solution containing amino acids excluding L-tyrosine, vitamin C and pantothenic acid in the A chamber, reducing sugar in the B chamber, L-tyrosine, vitamin B ₁ , vitamin B ₂ , vitamin B ₆ and nicotinic acids. Infusion containing vitamin A, vitamin D, vitamin E, vitamin K, vitamin B ₁₂ in the C chamber, and the infusion in the A and / or B chambers further containing electrolyte A nutritional infusion is disclosed.

Patent Document 4 discloses an infusion consisting of three solutions of a solution containing a reducing sugar, a solution containing an amino acid, and a solution containing a fat-soluble vitamin, wherein the reducing sugar solution contains vitamin B ₁ and the amino acid solution is There is described an infusion for central administration in which folic acid is contained, fat-soluble vitamin liquid contains vitamin C, and vitamin B ₂ is blended with an amino acid liquid or a fat-soluble vitamin liquid.

Further, Patent Document 5 discloses an infusion solution consisting of three solutions of a solution containing a reducing sugar, a solution containing an amino acid, and a solution containing vitamin D, wherein the reducing sugar solution further contains vitamin B ₁ and an amino acid solution. Further describes vitamin B ₁₂ , folic acid, and vitamin D solution further containing other fat-soluble vitamins, vitamin B ₂ and vitamin C.

Of these, the infusion described in Patent Documents 1 to 3, but is intended to incorporate vitamin B ₂ in a reducing sugar solution or amino acid solution, vitamin B ₂ itself is yellow, the naturally dissolving the solution yellow Therefore, even when reducing sugars and amino acids are decomposed, there is a problem that coloring caused by the decomposition cannot be recognized or discriminated. Moreover, since a liquid with a relatively large volume becomes yellow, there is a concern that all liquids may be mistakenly mixed and only one liquid may be administered without mixing.

On the other hand, infusion described in Patent Document 4 or 5, vitamin B ₂ for the amino acid solution and the reducing sugar solution is obtained by accommodating the different small containers, the above problem would not occur. However, this infusion solution is a fat-soluble vitamin solution containing vitamin C contained in a small container. The fat-soluble vitamin is stabilized, but conversely, vitamin B ₂ contained in the small container is vitamin C. There exists a problem that it becomes easy to be oxidized with oxygen by influence. In particular, when the small container is divided into two chambers and the trace metal element preparation is accommodated in one chamber, it is necessary to arrange the small container itself on the reducing sugar solution side for stabilization. since antioxidants such as normal sulfite is not added, there is a possibility that the dissolved oxygen influences the vitamin B _2.
JP 2000-273035 A JP 2001-55328 A JP 2001-163780 A Japanese Patent Laid-Open No. 11-158061 International Publication WO99 / 39679 Pamphlet

The present invention provides a stable comprehensive infusion preparation that is free from the risk of misadministration despite the incorporation of amino acids, reducing sugars, fat-soluble vitamins, vitamin B ₂ , vitamin C, and the like.

As a result of various studies to solve the above-mentioned problems, the present inventors have found that the reducing sugar solution (A) and the amino acid solution (B) separately contained in the two chambers separated by the communicating partition wall, and the above-mentioned It is equipped with a fat-soluble vitamin solution (C) contained in a small container that can communicate with either one of the two chambers, vitamin B ₂ is blended with the fat-soluble vitamin solution, and vitamin C is reduced sugar solution (A) or amino acid solution. It was found that by blending with (B), an excellent comprehensive infusion preparation with no fear of misperception due to forgetting to blend can be obtained. Based on this knowledge, further studies have been made and the present invention has been completed.

That is, the present invention relates to the following general infusion preparations [1] to [11].
[1] Reducing sugar solution (A) and amino acid solution (B) separately contained in each chamber of a container having two chambers separated by a communicating partition wall, and a small size capable of communicating with either one of the two chambers It is provided with a fat-soluble vitamin liquid (C) contained in a container, wherein vitamin B ₂ is blended in the fat-soluble vitamin liquid (C) and vitamin C is blended in the reducing sugar liquid (A) or amino acid liquid (B). A comprehensive infusion formulation,
[2] The general infusion preparation according to [1], wherein vitamin C is blended in the amino acid solution (B),
[3] The container is formed of a flexible thermoplastic film, and the communicating partition wall is configured to seal the opposing inner wall surfaces of the container body so as to be peeled from each other, and the small container is formed of flexible heat. It is formed of a plastic film, and is fixed to each of the opposing inner wall surfaces of the container body in the vicinity of the partition wall where the container can communicate, and the small container is opened as the inner wall surface is separated as the partition wall is opened. The comprehensive infusion preparation according to [1] or [2], wherein
[4] A chamber in which the small container is divided into two chambers, the fat-soluble vitamin liquid (C) is stored in one chamber, the trace metal element preparation is stored in the other chamber, and the reducing sugar solution (A) in the container is stored. A comprehensive infusion preparation according to the above [3],
[5] The general infusion preparation according to [4], wherein iodine is blended in the reducing sugar solution (A) or the amino acid solution (B),
[6] The comprehensive infusion preparation according to any one of [1] to [5], wherein the reducing sugar in the reducing sugar liquid (A) is glucose.
[7] The amino acid in the amino acid solution (B) is L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, L-valine, L-alanine, L- The general infusion according to any one of [1] to [6], which is arginine, L-aspartic acid, L-cysteine, L-glutamic acid, L-histidine, L-proline, L-serine, L-tyrosine and glycine. Formulation,
[8] The general infusion preparation according to any one of [1] to [7], wherein the fat-soluble vitamin in the fat-soluble vitamin liquid (C) is vitamin A, vitamin D, vitamin E, and vitamin K,
[9] The comprehensive infusion preparation according to any one of the above [4], wherein the trace metal elements in the trace metal element liquid (D) are iron, manganese, zinc and copper,
[10] The reducing sugar solution (A) further contains vitamin B ₁ , vitamin B ₆ , vitamin B ₁₂ , panthenol and iodine, and the amino acid solution (B) further contains ascorbic acid, folic acid and nicotinic acid amide [9] And [11] the general infusion preparation according to [10], wherein the component composition when all the solutions (A) to (D) are mixed is in the following range:

The comprehensive infusion preparation of the present invention is a stable comprehensive infusion preparation containing amino acids, reducing sugars, and various vitamins (including fat-soluble vitamins, vitamin B ₂ and vitamin C), and also contains vitamin vitamin B ₂ . Nevertheless, it is possible to recognize and distinguish coloring based on the decomposition of amino acids and reducing sugars, and thus prevent erroneous administration due to forgetting to mix.

The comprehensive infusion preparation of the present invention comprises a reducing sugar solution (A) and an amino acid solution (A) separately contained in each chamber of a container having two chambers (also referred to as a first chamber and a second chamber) separated by a communicating partition wall. B) and a fat-soluble vitamin solution (C) housed in a small container capable of communicating with either one of the two chambers, vitamin B ₂ is a fat-soluble vitamin solution (C), and vitamin C is a reducing sugar solution (A) or an amino acid solution (B).

  Examples of the reducing sugar contained in the reducing sugar solution (A) include monosaccharides such as glucose and fructose, and disaccharides such as maltose. Among them, glucose, fructose and maltose are preferable, and glucose is particularly preferable in terms of blood glucose control. Is preferred. These reducing sugars may be used as a mixture of two or more, and a mixture obtained by adding sorbitol, xylitol, glycerin and the like to these reducing sugars may be used.

  The reducing sugar is preferably blended in the solution in which all the solutions are mixed so as to be about 20 to 800 g / L, preferably about 50 to 400 g / L.

  This reducing sugar solution (A) has a pH of about 2-6, preferably using an ordinary pH adjuster, for example, acids such as hydrochloric acid, acetic acid, lactic acid, malic acid, citric acid and alkalis such as sodium hydroxide as appropriate. It is preferable to adjust to about 2.5-5.

  Examples of the amino acid contained in the amino acid solution (B) include essential amino acids, non-essential amino acids, and / or salts, esters, or N-acyl compounds and the like can be mentioned. 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, glycine and the like. These amino acids include inorganic acid salts such as L-arginine hydrochloride, L-cysteine hydrochloride, L-glutamine hydrochloride, L-histidine hydrochloride, L-lysine hydrochloride, L-lysine acetate, L-lysine. Organic acid salts such as malate, ester forms such as L-tyrosine methyl ester, L-methionone methyl ester, L-methionine ethyl ester, N-acetyl-L-cysteine, N-acetyl-L-tryptophan, N- Also in the form of dipeptides such as N-substitutes such as acetyl-L-proline, L-tyrosyl-L-tyrosine, L-alanyl-L-tyrosine, L-arginyl-L-tyrosine, L-tyrosyl-L-arginine good.

  It is preferable that the amino acid is blended in the following blending amount (in terms of free form) in a solution obtained by mixing all the solutions. L-leucine about 0.4-20.0 g / L, preferably about 0.8-10.0 g / L, L-isoleucine about 0.2-14.0 g / L, preferably about 0.4-7. 0 g / L, L-valine about 0.1-16.0 g / L, preferably about 0.3-8.0 g / L, L-lysine about 0.2-14.0 g / L, preferably about 0.0. 5 to 7.0 g / L, about 0.1 to 8.0 g / L of L-threonine, preferably about 0.3 to 4.0 g / L, about 0.04 to 3.0 g / L of L-tryptophan, Preferably about 0.08-1.5 g / L, L-methionine about 0.1-8.0 g / L, preferably about 0.2-4.0 g / L, L-phenylalanine about 0.2-12. 0 g / L, preferably about 0.4 to 6.0 g / L, L-cysteine about 0.01 to 2.0 g / L, preferably about 0.03 to 1.0 g L, L-tyrosine about 0.01-2 g / L, preferably about 0.02-1.0 g / L, L-arginine about 0.2-14.0 g / L, preferably about 0.5-7. 0 g / L, about 0.1-8.0 g / L of L-histidine, preferably about 0.3-4.0 g / L, about 0.2-14.0 g / L of L-alanine, preferably about 0.0. 4 to 7.0 g / L, L-proline about 0.1 to 10.0 g / L, preferably about 0.2 to 5.0 g / L, L-serine about 0.1 to 6.0 g / L, preferably Is about 0.2 to 3.0 g / L, glycine is about 0.1 to 12.0 g / L, preferably about 0.3 to 6.0 g / L, and L-aspartic acid is about 0.01 to 4.0 g / L. , Preferably about 0.03 to 2.0 g / L, L-glutamic acid about 0 to 6.0 g / L, preferably about 0 to 3.0 g / L. Preferred.

  The pH of the amino acid solution (B) is about 2.5 to 10 using an ordinary pH adjuster, for example, acids such as hydrochloric acid, acetic acid, lactic acid, malic acid, succinic acid, citric acid, and alkalis such as sodium hydroxide as appropriate. It is preferable to adjust to about 5-8.

Examples of the fat-soluble vitamin contained in the fat-soluble vitamin liquid (C) include vitamin A, vitamin D, vitamin E, vitamin K, and the like. Examples of vitamin A include ester forms such as palmitic acid ester and acetic acid ester. Examples of vitamin D include vitamin D ₁ , vitamin D ₂ , vitamin D ₃ (cholecalciferol), and active forms thereof (hydroxy derivatives). Examples of vitamin E (tocopherol) include ester forms such as acetate ester and succinate ester. Examples of vitamin K (phytonadione) include derivatives such as phytonadione, menatetrenone, and menadione.

  These fat-soluble vitamins contain about 400 to 6500 IU / L, preferably about 800 to 6500 IU / L, more preferably about 800 to 4000 IU / L, vitamin D (core). About 0.5 to 10.0 μg / L, preferably about 1.0 to 10.0 μg / L, more preferably about 1.0 to 6.0 μg / L, vitamin E (as tocophenol acetate) ) About 1.0-20.0 mg / L, preferably about 2.5-20.0 mg / L, more preferably about 2.5-12.0 mg / L, and vitamin K (as phytonadione) about 0.0. It is preferable to add 2 to 4.0 mg / L, preferably about 0.5 to 4.0 mg / L, more preferably about 0.5 to 2.5 mg / L.

In the present invention, vitamin B ₂ is incorporated into fat-soluble vitamin solution (C), vitamin C is formulated in a reducing sugar solution (A) or amino acid solution (B). Examples of vitamin B ₂ include phosphate esters, sodium salts thereof, flavin mononucleotides, and flavin adenine dinucleotides. Examples of vitamin C include ascorbic acid or sodium ascorbate.

Vitamin B ₂ and Vitamin C are mixed in a solution containing all the solutions, and vitamin B ₂ (as riboflavin) is about 0.5 to 6.0 mg / L, preferably about 1.0 to 6.0 mg / L, More preferably about 1.0-4.0 mg / L, vitamin C (as ascorbic acid) about 12-200 mg / L, preferably about 25-200 mg / L, more preferably about 25-120 mg / L It is preferable to blend in.

In the present invention, various water-soluble vitamins can be blended in addition to the aforementioned fat-soluble vitamins (that is, vitamin A, vitamin D, vitamin E, vitamin K), vitamin B ₂ and vitamin C. Examples of such water-soluble vitamins include vitamin B ₁ , pantothenic acids, vitamin B ₆ , nicotinic acids, vitamin B ₁₂ , folic acid, biotin (vitamin H), and the like. Examples of vitamin B ₁ include thiamine hydrochloride, prosultiamine, and octothiamine. Examples of pantothenic acids include the form of panthenol, which is a calcium salt or a reduced form, in addition to the free form. Examples of vitamin B ₆ include salt forms such as pyridoxine hydrochloride. Examples of nicotinic acids include nicotinic acid or nicotinic acid amide. The vitamin _{B 12,} for example, cyanocobalamin and the like.

These water-soluble vitamins contain about 0.4 to 30.0 mg / L, preferably about 0.8 to 30.0 mg / L, of vitamin B ₁ (as thiamine hydrochloride) in a mixed solution. More preferably, about 1.0-5.0 mg / L, pantothenic acids (as pantothenic acid) is about 1.5-35.0 mg / L, preferably about 3.0-30.0 mg / L, vitamin B ₆ ( About 0.5 to 8.0 mg / L, preferably about 1.0 to 8.0 mg / L, more preferably about 1.0 to 5.0 mg / L, as nicotinic acids (as nicotinamide) ) About 5.0-80.0 mg / L, preferably about 10.0-80.0 mg / L, more preferably about 10.0-50.0 mg / L, and vitamin B ₁₂ (as cyanocobalamin) about 0 .5 to 50.0 μg / , Preferably about 1.0-20.0 μg / L, more preferably about 1.0-10.0 μg / L, folic acid about 50-800 μg / L, preferably about 100-800 μg / L, more preferably about It is preferable to add 100 to 120 μg / L and biotin to a concentration of about 5 to 120 μg / L, preferably about 15 to 120 μg / L, preferably about 15 to 70 μg / L.

  In the present invention, in addition to the reducing sugar, amino acid and vitamins (fat-soluble vitamins and water-soluble vitamins), trace metal elements can be further blended.

  Examples of the trace metal element include iron, manganese, zinc, copper, and iodine. Among these trace metal elements, examples of the iron supply source include ferric chloride and ferric sulfate, and examples of the manganese supply source include manganese chloride and manganese sulfate. Examples of the source include zinc chloride and zinc sulfate. Examples of the source of copper include copper sulfate. Examples of the source of iodine include potassium iodide.

  These trace metal elements may be used alone or in combination of two or more according to the condition of the subject patient. The compounding amount of the trace metal is not particularly limited as long as it is within a general range as the dose (daily required amount) of each trace metal element per day described in various documents in the field of infusion. If the compounding amount is exemplified, iron (as an iron source) is added in an amount of about 2 to 200 μmol / L, preferably about 5 to 100 μmol / L, and manganese (as a manganese source) in a mixed solution of all the solutions. About 0-10 μmol / L, preferably about 0-5 μmol / L, zinc (as zinc source) is about 2-300 μmol / L, preferably about 1-150 μmol / L, copper (as copper source) is about 0 0.5 to 40 μmol / L, preferably about 1 to 20 μmol / L, iodine (as iodine source) is preferably about 0 to 5 μmol / L, preferably about 0.2 to 5 μmol / L .

  Among the above trace metal elements, iron, manganese and copper are separated from the fat-soluble vitamin liquid (C) by dividing the small container into two chambers (third chamber and fourth chamber) as shown in FIG. It is preferable to accommodate. That is, it is preferable to store the fat-soluble vitamin liquid (C) in the third chamber and the trace metal element liquid (D) containing iron, manganese and copper in the fourth chamber. Iodine is preferably separated from at least copper, and is suitably blended in, for example, the reducing sugar solution (A). Zinc can be added to the reducing sugar solution (A) or the amino acid solution (B), but is preferably added to the trace metal element solution (D).

Fat-soluble vitamins, vitamin B ₂ and vitamin various water-soluble vitamins other than C can be formulated as follows.

Vitamin B ₁ can be blended in a reducing sugar solution (A), a fat-soluble vitamin solution (C) or a trace metal element solution (D), and particularly in reducing sugar solution (A) or a fat-soluble vitamin solution (C). It is preferable to mix | blend, and it is preferable to mix | blend with reducing sugar liquid (A) especially. The liquid containing vitamin B ₁ preferably contains no sulfite and has a pH of about 3.5 to 5.5.

Vitamin B ₆ may be added to any of the reducing sugar solution (A), the amino acid solution (B), the fat-soluble vitamin solution (C), and the trace metal element solution (D). It is preferable to mix.

Vitamin B ₁₂ is preferably incorporated in an amount of the reducing sugar solution (A) or fat-soluble vitamin solution (C), preferably in particular be incorporated into the reducing sugar solution (A). However, it is desirable to avoid coexistence with vitamin C. Therefore, when blended vitamin B ₁₂ in the reducing sugar solution (A), 1 Vitamin C is preferably blended in an amino acid solution (B).

  Biotin (vitamin H) may be added to any of the reducing sugar solution (A), the amino acid solution (B), the fat-soluble vitamin solution (C), and the trace metal element solution (D). ) Is preferable.

  Pantothenic acids may be incorporated into any of the reducing sugar solution (A), the amino acid solution (B), the fat-soluble vitamin solution (C), and the trace metal element solution (D). It is preferable to do this.

  Nicotinic acids may be added to any of the reducing sugar solution (A), the amino acid solution (B), the fat-soluble vitamin solution (C), and the trace metal element solution (D), but it is added to the amino acid solution (B). Is preferred.

  Folic acid is preferably added to the amino acid solution (B), the fat-soluble vitamin solution (C) or the trace metal element solution (D), and particularly preferably added to the amino acid solution (B).

In the general infusion preparation of the present invention, a preferable blending example is that, when divided into three chambers and filled, the reducing sugar solution (A) includes vitamin B ₁ , vitamin B ₆ , vitamin B ₁₂ , pantothenic acids in addition to glucose. The amino acid solution (B) contains L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, L-valine, L-alanine, L -Contains vitamin C and nicotinic acids in addition to amino acids consisting of arginine, L-aspartic acid, L-cysteine, L-glutamic acid, L-histidine, L-proline, L-serine, L-tyrosine, glycine, and is fat-soluble vitamin solution (C) is vitamin a, vitamin D, vitamin B ₂ in addition to vitamin E, fat soluble vitamins consisting of vitamin K It includes those containing biotin.

In addition, when a trace metal element liquid (D) is used and divided into four chambers, the reducing sugar liquid (A) contains vitamin B ₁ , vitamin B ₆ , vitamin B ₁₂ as vitamins in addition to glucose. Pantothenic acids contain iodine (as potassium iodide) as a trace metal element. The amino acid solution (B) contains L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L -From 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, glycine It contains vitamin C and nicotinic acids as vitamins in addition to the amino acids that are used, and fat-soluble vitamin liquid (C) contains vitamin A and vitamin D, contains vitamin B ₂ in addition to vitamin E, fat soluble vitamins consisting of vitamin K, containing biotin to trace metals solution (D) iron, manganese, zinc, as well vitamins trace metals of copper The thing which was done is mentioned.

In the present invention, an electrolyte can be further blended in addition to reducing sugars, amino acids, vitamins (fat-soluble vitamins, water-soluble vitamins), and trace metal elements. Examples of the electrolyte include a cation such as sodium ion (Na ⁺ ), potassium ion (K ⁺ ), calcium ion (Ca ²⁺ ), and magnesium ion (Ma ²⁺ ), an anion such as chlor ion (Cl ⁻ ), and phosphorus ( P). Examples of the sodium ion supply source include sodium chloride, sodium acetate, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium lactate. Examples of the potassium ion source include potassium chloride, potassium acetate, potassium citrate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium sulfate, and potassium lactate. Examples of the calcium ion supply source include calcium chloride, calcium lactate, calcium pantothenate, calcium lactate, and calcium acetate. Examples of the magnesium ion supply source include magnesium sulfate, magnesium chloride, and magnesium acetate. Examples of the phosphorus source include phosphorus compounds such as sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium glycerophosphate.

  These electrolytes have a potassium ion content of about 5 to 80 mEq / L, preferably about 20 to 80 mEq / L, preferably about 20 to 80 mEq / L, in a mixed solution of all the solutions. Magnesium ions are about 1-40 mEq / L, preferably about 2-20 mEq, so that calcium ions are about 1-40 mEq / L, preferably about 2-20 mEq / L, so that about 10-40 mEq / L. So that phosphorus is about 1 to 40 mmol / L, preferably about 2 to 20 mmol / L, and chlor ion is about 10 to 160 mEq / L, preferably about 20 to 80 mEq / L. It is preferable to blend in.

  Of these electrolytes, the calcium salt and the magnesium salt are preferably separated from the phosphorus compound and blended in different solutions. Other electrolytes are not particularly limited, and may be blended in any of solutions (A) to (C).

  In addition, sulfite and / or bisulfite can be added to the amino acid solution (B) as a stabilizer, and in that case, 50 mg / L or less is preferably added to the amino acid solution (B).

As a preferable specific example of the general infusion preparation of the present invention, the reducing sugar solution (A) contains glucose, vitamin B ₁ , vitamin B ₆ , vitamin B ₁₂ , panthenol and iodine (as potassium iodide), and an amino acid solution (B) includes L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, L-valine, L-alanine, L-arginine, L-aspartic acid, L -Contains cysteine, L-glutamic acid, L-histidine, L-proline, L-serine, L-tyrosine, glycine, nicotinic acid amide, folic acid and ascorbic acid. Contains D, Vitamin E, Vitamin K and Vitamin B ₂ and contains trace metal element liquid (D) with iron, manganese, Mention may be made of infusions containing lead, copper and biotin.

As another preferable specific example of the comprehensive infusion preparation of the present invention, the reducing sugar solution (A) contains glucose, vitamin B ₁ , vitamin B ₆ , vitamin B ₁₂ and panthenol, and the amino acid solution (B) contains 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, glycine, nicotinamide, folic acid and ascorbic acid, vitamin A, vitamin D, vitamin E, vitamin in fat-soluble vitamin liquid (C) K, may be mentioned infusate containing vitamin B ₂ and biotin.

As a more preferable specific example of the general infusion preparation of the present invention, each component is blended in 1 L of the infusion solution after mixing all the solutions (A) to (D) so as to fall within the ranges shown in Table 2 below. Can be mentioned.

Moreover, as a preferable specific example of the comprehensive infusion preparation of the present invention in which no trace metal element solution (D) is blended, each component is as follows in 1 L of infusion after mixing all the solutions (A) to (C). The infusion agent mix | blended so that it may become the range of Table 3 can be mentioned.

  The container of the general infusion preparation according to the present invention has two chambers for storing the reducing sugar solution (A) and the amino acid solution (B) separated by a partition wall that can communicate, and any one of the two chambers. If it has a small container for accommodating the fat-soluble vitamin liquid (C) which can communicate with one side, it will not specifically limit. The small container may be further divided into two chambers for separately storing the fat-soluble vitamin liquid (C) and the trace metal element liquid (D), or the fat-soluble vitamin liquid (C) and Two small containers may be provided to accommodate the trace metal element liquid (D) separately.

  Such containers are not particularly limited, and for example, those described in Japanese Patent Application Laid-Open No. 11-158061 and International Publication WO99 / 39679 can be adopted. Along with the opening of the small container, the one described in the pamphlet of International Publication No. WO2003 / 092574 is cited.

  One mode of an infusion container that contains the comprehensive infusion preparation of the present invention will be specifically described with reference to the drawings. FIG. 1 is a plan view of an infusion container, which has two chambers (first chamber and second chamber) separated by a partition wall (5) capable of communicating, and can be connected to either one of the two chambers. A small container (6) is provided. Either the first chamber (3) or the second chamber (4) is filled with the reducing sugar solution (A), and the other chamber is filled with the amino acid solution (B). It is preferable to fill the reducing sugar solution (A) in 3) and the amino acid solution (B) in the second chamber (4) as the lower chamber. Further, the small container (6) is filled with the fat-soluble vitamin liquid (C), but the small container (6) is divided into two chambers as shown in FIG. 2, and one chamber (the third chamber (6a)). ) May be filled with the fat-soluble vitamin liquid (C), and the other chamber (fourth chamber (6b)) may be filled with the trace metal element solution (D). The small container (6) is provided on the first chamber side when the first chamber (3) is filled with the reducing sugar solution (A) and the second chamber (4) is filled with the amino acid solution (B). Are preferred.

  The closed chemical solution inflow portion (9) communicating with the first chamber (3) is used for injecting another drug using a syringe or the like, and the closed chemical solution communicating with the second chamber (4) is used. The outflow part (8) is used for connecting with an infusion set for injecting an internal drug solution into a patient, and for injecting another drug using a syringe or the like.

  As a material for the body (2) of the infusion container, various flexible thermoplastics conventionally used in medical containers and the like can be used. For example, polyethylene or a copolymer thereof, polypropylene or a copolymer thereof, polyvinyl chloride Saponified polyvinyl alcohol, mixture of polypropylene and polyethylene or polybutene, olefinic resin or partially crosslinked polyolefin such as ethylene-propylene copolymer, styrene elastomer, polyester such as polyethylene terephthalate or soft vinyl chloride resin, or the like Of these, a material in which an appropriate resin is mixed, or a sheet obtained by molding the material in multiple layers including other materials such as nylon and cyclic olefin copolymer can be used.

  The communicable partition wall (5) provided between the first chamber (3) and the second chamber (4) is formed by pressing either the first chamber (3) or the second chamber (4). For example, what is comprised by weakly sealing the inner wall surfaces which a container main body opposes so that peeling is suitable is mentioned.

  The small container (6) is connected to one of the two chambers containing the reducing sugar solution (A) and the amino acid solution (B) in a connectable manner. Such a small container is not particularly limited. For example, the small container is formed of a flexible thermoplastic film and is fixed to each of the opposing inner wall surfaces of the container body (2) in the vicinity of the partition wall (5) capable of communicating. It is preferable to open the partition wall 5 as the inner wall surface is separated. An example of the infusion container provided with such a small container is a container described in WO03 / 092574. 3 is a cross-sectional view taken along line AA in FIG.

  The material of the small container (6) can be the same as the material of the infusion container main body, but is particularly easy to open with the separation of the inner wall surface associated with the opening of the partition wall (5), such as polycyclic olefin or polypropylene. A film having a multilayer structure in which is sandwiched between polyethylene is preferably mentioned.

  For example, as shown in FIG. 3A, the infusion container including the small container as described above has one end portion of the small container 6 as a film (2a) (2b) constituting the first chamber (3). ) Is heat-sealed to the inner wall surface, and this fused portion forms a fixing portion (7). This adhering portion (7) is fused in the vicinity of the weakly sealed partition wall (5) with a strength stronger than that of the partition wall (5) and usually not peeling.

  A method of using the infusion container configured as described above will be described. First, the first chamber or the second chamber is pressed by hand to increase the pressure in the chamber. Thereby, the partition wall (5) of the seal portion is opened, the first chamber (3) and the second chamber (4) are communicated, and the reducing sugar solution (A) and the amino acid solution (B) are mixed. At this time, the partition wall (5) is opened by separating the films (2a) and (2b) of the container body (2), and the small container (6) is opened accordingly. That is, as shown in FIG. 3B, when the films (2a) and (2b) of the container main body are separated from each other, a force F accompanying the separation acts on the small container (6). At this time, since the two multilayer films (6a) and (6b) of the small container (6) are fixed to the films (2a) and (2b) of the container body (2) by the fixing portion (7), The films (6a) and (6b) are separated together with the films (2a) and (2b) of the container body (2). As a result, the multilayer films (6a) and (6b) constituting the small container (6) cause delamination, and the multilayer film is broken accordingly. In this way, the fat-soluble vitamin liquid (C) sealed in the small container (6) is mixed into the mixed liquid of the reducing sugar liquid (A) and the amino acid liquid (B) mixed as described above. Subsequently, when a puncture needle (not shown) having a conduit connected to a rubber stopper (not shown) of the drug solution outlet (8) is inserted, the mixed drug solution is administered to the patient via the conduit.

  As shown in FIG. 2, the small container (6) is divided into two chambers, one chamber (third chamber) is filled with fat-soluble vitamin liquid (C), and the other chamber (fourth chamber) is trace metal. Although the elemental liquid (D) may be filled, in this case, the small container (6) may be partitioned by the partition weak seal as described above. Instead of using a small container with a partition, two small containers are provided, one small container is filled with a fat-soluble vitamin liquid (C), and the other small container is filled with a trace metal element liquid (D). You can also

  The infusion solution of the present invention contained in the container as described above is preferably packaged with a gas-impermeable outer bag together with an oxygen scavenger in order to reliably prevent alteration, oxidation, etc. When the partition is formed by easy-peeling welding, it is preferable to wrap the partition in a folded state so that the partition does not communicate with the external pressure. Moreover, inert gas filling packaging etc. can also be performed as needed.

  As a material suitable for the outer bag, a generally used gas-impermeable film or sheet can be used. For example, ethylene / vinyl alcohol copolymer (EVOH), polyvinylidene chloride (PVDC), polyacrylonitrile. , Polyvinyl alcohol (PVA), polyamide, polyethylene terephthalate (PET), polyethylene naphthalate (PEN), polyester, nylon, or a film or sheet containing at least one of gas-impermeable materials, or a multilayer film, or silica Examples thereof include those subjected to vapor deposition or alumina vapor deposition, and can be appropriately selected and used.

  Furthermore, it is preferable to provide the outer bag with a light shielding property. In order to give the outer bag light-shielding properties, for example, aluminum film can be deposited on the film or sheet, or an aluminum laminate film or a polyester film mixed with carbon black or the like can be used.

  The shape and size of the outer bag are not particularly limited as long as the general infusion container can be accommodated. Preferably, the size is about 1.2 to about 3 times the volume of the container.

  Examples of the oxygen scavenger enclosed in the outer bag include (1) iron carbide, iron carbonyl compound, iron oxide, iron powder, iron hydroxide or silicon iron coated with a metal halide, and (2) hydroxylation. Alkaline earth metal or alkaline earth metal carbonate, mixture of alkaline substance or alcohol compound and nitrite, (3) ferrous compound, transition metal salt, aluminum salt, alkali metal or alkaline earth metal A mixture of an alkaline compound containing nitrogen, an alkaline compound containing nitrogen or an ammonium salt and an alkaline earth metal sulfite, (4) a mixture of iron or zinc and sodium sulfate monohydrate, or a mixture of the mixture and a metal halide (5) Iron, copper, tin, zinc or nickel; sodium sulfate heptahydrate or decahydrate; and metal halide mixture (6) transition metal of period 4 of the periodic table; tin or antimony; or a mixture of the mixture and metal halide, (7) alkali metal or ammonium sulfite, bisulfite or pyrosulfite; transition Metal salts or aluminum salts can be used. From these known materials, it can be appropriately selected as desired. As the oxygen scavenger, it is preferable to use it in a suitable air-permeable sachet as long as it is in powder form, and it may be used as it is without packaging if it is tableted.

  Commercially available oxygen scavengers can be used. Examples of such commercially available oxygen scavengers are Ageless (manufactured by Mitsubishi Gas Chemical Company), Modulan (manufactured by Nippon Kayaku Co., Ltd.), Vitalon (Toagosei Chemical). Kogyo Co., Ltd.), Tamotsu (Oji Chemical Co., Ltd.), Sanso Cut (Finetech Co., Ltd.), Secur (Nihon Soda Co., Ltd.), Oxyguard (Toyo Seikan Co., Ltd.), High Leto Flex-RD (Toyo) Etc.).

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated, this invention is not limited to these Examples.

<Example 1>
(1) Preparation of reducing sugar solution (A) Glucose and electrolyte (sodium chloride, potassium chloride, potassium dihydrogen phosphate, potassium iodide) are dissolved in water for injection, and vitamin B ₁ (thiamine hydrochloride), vitamin B ₆ (pyridoxine hydrochloride), vitamin B ₁₂
(Cyanocobalamin) and panthenol were dissolved and adjusted to pH 4 with acetic acid, followed by sterile filtration to prepare a reducing sugar solution (A) having the composition shown in Table 4.

(2) Preparation of amino acid solution (B) Each crystalline amino acid and electrolyte (potassium chloride, magnesium sulfate, potassium acetate) are dissolved in distilled water for injection, and vitamin C (ascorbic acid), folic acid, and nicotinamide are added. After dissolution, the mixture was adjusted to pH 6.5 with succinic acid and sterile filtered to prepare an amino acid solution (B) having the composition shown in Table 5. To the solution (B), sodium bisulfite was added as a stabilizer so as to have a concentration of 50 mg / L.

(3) Preparation of fat-soluble vitamin liquid (C) Apart from the liquid (A) and liquid (B), vitamin A (retinol palmitate), vitamin D ₃ (cholecalciferol), vitamin E (tocopherol acetate) and Vitamin K (phytonadione) is mixed with polysorbate 80 (concentration in liquid (C) = 5 mg / mL), polysorbate 20 (concentration in liquid (C) = 1 mg / mL) and polyethylene glycol 400 (macrogol 400). Then, a small amount of distilled water for injection was added to solubilize. Furthermore, vitamin B _{2 in} distilled water for injection
(Sodium riboflavin phosphate) and D-sorbitol were dissolved, adjusted to pH 6 with citric acid and sodium hydroxide, and then mixed with the solubilized solution. This solution was aseptically filtered to prepare a fat-soluble vitamin solution (C) having the composition shown in Table 6.

(4) Preparation of trace metal element solution (D) Injected aqueous solution of chondroitin sulfate for injection into distillate solution for injection of ferric chloride and distillate solution for injection of sodium hydroxide, 1 in order from sodium hydroxide solution first. A predetermined amount of ferric chloride was added while alternately adding / 10 amounts. After adding predetermined amounts of copper sulfate, manganese chloride, zinc sulfate and biotin to this solution as solutions of water for injection, the pH was adjusted to 5.3 with sodium hydroxide and filtered by a conventional method as shown in Table 7. A solution having the following composition was prepared. In addition, sodium chondroitin sulfate was added so as to have a concentration of 2.5 g / L.

(4) Filling / Packaging Each of the fat-soluble vitamin liquid (C) and the trace metal element liquid (D) is formed in a two-chamber small container formed from a 50 μm thick film whose intermediate layer is made of polycyclic olefin and whose inner and outer layers are made of polyethylene. 4 mL was separately charged and melted and closed. Next, the small container was inserted into the first chamber of the two-chamber infusion bag made of polyethylene and welded to both wall surfaces of the bag. Subsequently, 692 mL of the reducing sugar solution (A) was filled in the first chamber in which the small container was inserted, and 300 mL of the amino acid solution (B) was filled in the second chamber, and each was sealed so that the headspace portion was 0 mL. A comprehensive infusion formulation in a container like 2 was obtained.

<Example 2>
(1) Preparation of reducing sugar solution (A) A reducing sugar solution (A) having the composition shown in Table 8 was prepared in the same manner as in Example 1.
(2) Preparation of amino acid solution (B) In the same manner as in Example 1, an amino acid solution (B) having the composition shown in Table 9 was prepared. In addition, sodium hydrogen sulfite was added to the amino acid solution (B) as a stabilizer so as to have a concentration of 50 mg / L.
(3) Preparation of fat-soluble vitamin liquid (C) A fat-soluble vitamin liquid (C) having the composition shown in Table 10 was prepared in the same manner as in Example 1.

(4) Filling / Packaging 4 mL of the liquid (C) was filled into a small container formed from a 50 μm thick film having an intermediate layer made of polycyclic olefin and an inner and outer layers made of polyethylene, and then closed. Next, the small container was inserted into one chamber of a polyethylene two-chamber infusion bag and welded to both wall surfaces of the bag. Subsequently, 300 mL of the liquid (B) was filled in the chamber into which the small container was inserted, and 696 mL of the liquid (A) was filled in the other chamber, and each was sealed so that the headspace portion was 0 mL, as shown in FIG. A containered infusion formulation was obtained.

<Comparative Example 1>
Comprehensive infusion solution in a container in the same manner as in Example 1 except that ascorbic acid is blended in the fat-soluble vitamin liquid (C) to a concentration of 12.5 mg / mL instead of blending in the amino acid liquid (B) Got.

<Comparative example 2>
Comprehensive infusion solution in a container as in Example 2 except that ascorbic acid is blended in the fat-soluble vitamin liquid (C) to a concentration of 12.5 mg / mL instead of blending in the amino acid liquid (B) Got.

<Test example>
For the general infusion preparations obtained in Examples 1 and 2 and Comparative Examples 1 and 2, 40 mL of gas having an oxygen concentration of 1%, 3%, and 5% was injected into the liquid in which a small container was inserted, and heated by a conventional method. After sterilization, it was packaged together with an oxygen scavenger in a gas barrier light-shielding bag (aluminum laminate bag). After leaving at room temperature for 1 week after packaging, the vitamin B ₂ content was measured by a general test method of the Japanese Pharmacopoeia: high performance liquid chromatography. Table 11 shows the vitamin B ₂ content after sterile package to vitamin B ₂ content of at unsterilized as residual rate.

<Discussion>
Vitamin B ₂ becomes unstable with respect to oxygen when combined with vitamin C (Comparative Examples 1 and 2). Therefore, when co-blended vitamin B ₂ and vitamin C, it must be strictly controlled oxygen concentration in the headspace. On the other hand, by blending a separate room of vitamin B ₂ and vitamin C as in Example 1 and 2 of the present invention is advantageous in that the headspace oxygen concentration may not be strictly controlled.

  The comprehensive infusion preparation of the present invention is useful as a pharmaceutical product.

It is a top view which shows one Embodiment of the container of the comprehensive infusion formulation which concerns on this invention. It is a top view which shows one Embodiment of the container of the comprehensive infusion formulation which concerns on this invention. It is the sectional view on the AA line of FIG.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 General infusion container 2 Container main body 3 1st chamber 4 2nd chamber 5 Bulkhead which can communicate (weak seal part)
6 Small container 7 Adhering part 8 Chemical liquid outflow part 9 Chemical liquid inflow part 10 Hanging hole 2a, 2b Film of container main body 6a, 6b Multilayer film of small container

Claims (10)

From the reducing sugar solution (A) and the amino acid solution (B) separately accommodated in each chamber of a container having two chambers separated by a partition wall that can communicate, and the two chambers that can communicate with either one of the two chambers Is also provided with a fat-soluble vitamin solution (C) contained in a small container having a small volume , vitamin B ₂ being a fat-soluble vitamin solution (C), vitamin B ₁ and vitamin B ₁₂ being a reducing sugar solution (A), vitamin Overall infusion preparation characterized in that it is formulated in C there amino acid solution (B). The container is formed of a flexible thermoplastic film, and the communicating partition wall is configured to seal the inner wall surfaces of the container body so as to be peelable, and the small container is a flexible thermoplastic film. The container is fixed to each of the opposing inner wall surfaces of the container main body in the vicinity of the partition wall where the container can communicate, and the small container is opened as the inner wall surface is separated as the partition wall is opened. The comprehensive infusion preparation according to claim 1, wherein The small container is divided into two chambers, a fat-soluble vitamin liquid (C) is stored in one chamber, a trace metal element liquid (D) is stored in the other chamber, and the small container is a reducing sugar solution (A The comprehensive infusion preparation according to claim 2 , which is disposed in a chamber containing The comprehensive infusion preparation according to claim 3 , wherein iodine is blended in the reducing sugar solution (A) or the amino acid solution (B). The comprehensive infusion preparation according to any one of claims 1 to 4 , wherein the reducing sugar in the reducing sugar liquid (A) is glucose. The amino acid in the amino acid solution (B) is L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, L-valine, L-alanine, L-arginine, L -A comprehensive infusion preparation according to any one of claims 1 to 5 , which is aspartic acid, L-cysteine, L-glutamic acid, L-histidine, L-proline, L-serine, L-tyrosine and glycine. The comprehensive infusion preparation according to any one of claims 1 to 6 , wherein the fat-soluble vitamins in the fat-soluble vitamin liquid (C) are vitamin A, vitamin D, vitamin E and vitamin K. The comprehensive infusion preparation according to claim 3 , wherein the trace metal elements in the trace metal element liquid (D) are iron, manganese, zinc and copper. Reducing sugar solution (A) is more vitamin B _1, vitamin B _6, vitamin B _12, include panthenol and iodine, amino acid solution (B) further ascorbic acid, according to claim 8 including a folic acid and nicotinic acid amide General infusion formulation. The comprehensive infusion preparation according to claim 9 , wherein the component composition when all the solutions (A) to (D) are mixed is in the following range.