Infusion preparation and production method for same

Abstract

The present invention provides a two-liquid mixture type infusion preparation in which precipitation is unlikely to occur even due to a change in composition upon addition of a calcium ion correction liquid. Provided as a solution is an infusion preparation which is for administration to a peripheral vein, which has two chambers that are separated by a partition that allows for communication, in which a first chamber infusion containing an amino acid is accommodated in a first chamber, and in which a second chamber infusion containing a sugar is accommodated in a second chamber, wherein a liquid mixture of the first chamber infusion and the second chamber infusion has (A) a pH of not more than 6.4 and (B) contains an organic acid in a total amount of not less than 3 mEq / L.

Description

Infusion preparation and its manufacturing method

[0001] The present invention relates to a two-liquid mixed infusion preparation containing at least an amino acid and a sugar, in which the mixed liquid is further mixed with a calcium ion correction solution, and to a method for producing the same.

[0002] When a fluid replacement with a special electrolyte composition is required, a correction electrolyte solution may be mixed with other infusion preparations so that the electrolyte solution can be added as needed depending on the individual case and an appropriate infusion can be administered (Patent Document 1).

[0003] It has been reported that caution is required when mixing Ca replacement fluid, Mg replacement fluid, etc. with other preparations, as this can cause incompatibility and lead to precipitation.

[0004] JP 2011-153083 A

[0005] Many infusion preparations for peripheral parenteral nutrition are designed to have replacement fluid added to the electrolyte solution of the infusion preparation, and normally, if the replacement fluid is added within an appropriate range, the above-mentioned precipitation does not occur and does not pose a problem. However, it is known that if replacement fluid is added to the electrolyte solution while the infusion bag is bent or if the replacement fluid is added to the electrolyte solution while the infusion bag is suspended, the mixing cannot be performed correctly, and the above-mentioned precipitation may occur, which may cause problems.

[0006] An object of the present invention is to provide a two-liquid mixed infusion preparation that is less likely to cause precipitation even when the formulation is changed by adding a calcium ion correction solution.

[0007] Through independent investigations, the present inventors have found that in a two-liquid mixed infusion preparation, by adjusting the mixed liquid to have a pH of 6.4 or less and to contain a total amount of organic acids of 3 mEq / L or more, precipitation is less likely to occur when the mixed liquid is mixed with a calcium ion correction solution.

[0008] That is, the present invention has been perfected through further improvements, and includes the aspects described in the following items. [Item 1] An infusion preparation for peripheral intravenous administration having two compartments separated by a communicable partition, wherein the first compartment contains a first compartment infusion solution containing an amino acid, and the second compartment contains a second compartment infusion solution containing a sugar, wherein a mixture of the first compartment infusion solution and the second compartment infusion solution: (A) has a pH of 6.4 or less; and (B) contains an organic acid in a total amount of 3 mEq / L or more. [Item 2] The infusion preparation for peripheral intravenous administration according to Item 1, wherein the organic acid has a carboxy group. [Item 3] The infusion preparation for peripheral intravenous administration according to Item 1 or 2, wherein the organic acid is a hydroxycarboxylic acid or acetic acid. [Item 4] The infusion preparation for peripheral intravenous administration according to any one of Items 1 to 3, wherein the pH of the mixture is 6.0 to 6.4. [Item 5] The infusion preparation for peripheral intravenous administration according to any one of Items 1 to 4, wherein the mixed solution contains at least one selected from citric acid, lactic acid, and acetic acid in a total amount of 55 mEq / L or more, or other organic acids in a total amount of 3 mEq / L or more. [Item 6] The infusion preparation for peripheral intravenous administration according to any one of Items 1 to 5, wherein the organic acid is gluconic acid and / or citric acid. [Item 7] The infusion preparation for peripheral intravenous administration according to any one of Items 1 to 6, wherein the mixed solution from which a total amount of 3 mEq / L or more of the organic acids has been removed has a pH of 6.7 or more. [Item 8] The infusion preparation for peripheral intravenous administration according to any one of Items 1 to 7, wherein the pH of the first compartment infusion solution is 6.55 or less. [Item 9] The mixed solution of the first compartment infusion solution and the second compartment infusion solution according to any one of Items 1 to 8, obtained by partition communication. [Item 10] The infusion preparation for peripheral intravenous administration according to any one of Items 1 to 8, wherein the mixed solution is used by mixing with a calcium ion correction solution. [Item 11] The infusion preparation for peripheral intravenous administration according to Item 10, wherein the ratio X / Y of the calcium ion content X (mEq / L) in the calcium ion correction solution to the organic acid content Y (mEq / L) in the mixed solution is 0.1 to 10.3.[Item 12] A method for producing an infusion preparation for peripheral intravenous administration, which has two compartments separated by a communicable partition, wherein a first compartment contains a first compartment infusion containing an amino acid, and a second compartment contains a second compartment infusion containing a sugar, wherein a mixture of the first compartment infusion and the second compartment infusion has: (A) a pH of 6.4 or less; and (B) an organic acid content of 3 mEq / L or more in total, the method comprising the step of changing the composition of the first compartment infusion and / or the second compartment infusion so that the pH of the mixture is 6.4 or less by adding an organic acid in a total amount of 3 mEq / L or more to the first compartment infusion and / or the second compartment infusion so that the pH of the mixture is 6.7 or more.

[0009] The infusion preparation of the present invention has the effect that when the mixed solution is used by mixing it with a calcium ion correction solution, precipitation is unlikely to occur even when the mixture is changed.

[0010] The present invention will be described in further detail below.

[0011] The present invention relates to an infusion preparation having two compartments separated by a communicable partition, the first compartment containing a first compartment infusion solution containing an amino acid, and the second compartment containing a second compartment infusion solution containing a sugar.

[0012] The infusion preparation of the present invention is characterized in that the mixture of the first compartment infusion solution and the second compartment infusion solution has: (A) a pH of 6.4 or less; and (B) a total amount of organic acids of 3 mEq / L or more. Due to these characteristics, the infusion preparation of the present invention exhibits the effect of being less likely to cause precipitation even when the mixture is mixed with a calcium ion correction solution.

[0013] <First Chamber Infusion Solution> The first chamber infusion solution used in the present invention contains an amino acid. The first chamber infusion solution contains an amino acid composition consisting of at least essential amino acids. The amino acids are contained at a concentration of 50 to 150 g / L, preferably 80 to 120 g / L, calculated as free amino acids. Each amino acid used is preferably a pure crystalline amino acid, as in general amino acid infusion solutions. While these are typically used in the form of free amino acids, they do not necessarily have to be in the free form; they can also be used in the form of pharmacologically acceptable salts, esters, N-acyl derivatives, salts of two amino acids, or peptides. In particular, L-cysteine ​​is preferably formulated in its N-acetyl form for stability. The volume of the first chamber infusion solution contained in the infusion container is preferably 100 to 500 mL. Distilled water for injection is typically used as the solvent for the first chamber infusion solution.

[0014] A preferred amino acid composition is, in terms of free amino acids, L-leucine: 5 to 20 (g / L), L-isoleucine: 3 to 15 (g / L), L-valine: 3 to 15 (g / L), L-lysine: 3 to 15 (g / L), L-threonine: 1.2 to 10 (g / L), L-tryptophan: 0.3 to 5 (g / L), L-methionine: 0.6 to 8 (g / L), L-phenylalanine: 1.8 to 15 (g / L), L-cysteine: 0.1 to 3 (g / L). (g / L), L-tyrosine: 0.06 to 2 (g / L), L-arginine: 3 to 15 (g / L), L-histidine: 1.2 to 10 (g / L), L-alanine: 3 to 15 (g / L), L-proline: 1.2 to 10 (g / L), L-serine: 0.6 to 7 (g / L), glycine: 1.2 to 10 (g / L), L-aspartic acid: 0.12 to 3 (g / L), L-glutamic acid: 0.12 to 3 (g / L).

[0015] If necessary, a small amount of a pH adjuster is added to the first chamber infusion solution to adjust the pH to 6.57 or less, preferably 6.57 to 6.06, and more preferably 6.46 to 6.06. The pH adjuster is preferably an organic acid. A pH of 6.55 or less has the effect of making it easier to maintain the pH after mixing within the optimum range described below.

[0016] In the present invention, the second chamber infusion fluid contains sugar. Specifically, for example, the second chamber infusion fluid may have a basic composition of glucose, strong electrolytes, and vitamin B1, and may not contain sulfite to stabilize vitamin B1.

[0017] In the above, glucose is used at a concentration of 80 to 200 g / L, preferably 80 to 150 g / L. It is preferable to keep the concentration of carboxylic acids and their salts in this glucose solution at 0 to 5 mEq / L to stabilize vitamin B1. Furthermore, to minimize buffering properties, it is preferable to adjust the pH of the glucose solution with a mineral acid such as hydrochloric acid, and further, to use strong electrolytes for all of the electrolytes. The pH of the second chamber infusion solution is in the range of 3 to 5, preferably 3.5 to 4.5. A pH below 3 improves the stability of vitamin B1 itself, but glucose becomes unstable. On the other hand, a pH above 5 impairs the stability of vitamin B1.

[0018] The volume of the glucose solution is preferably 200 to 1000 mL. Distilled water for injection is usually used as the solvent for the glucose solution. To further enhance the stability of vitamin B1 and to facilitate the adjustment of the pH of the mixed solution (described below) to 6 to 7.5, the titratable acidity of the glucose solution is preferably 1 or less, more preferably 0.5 or less, and even more preferably 0.1 or less.

[0019] Furthermore, in addition to glucose, one or more reducing sugars such as fructose and maltose, or non-reducing sugars such as sorbitol and glycerin may be added in an appropriate amount, if necessary.

[0020] Vitamin B1 is preferably added to the second chamber infusion solution at a concentration of 1 to 10 mg / L, preferably 2 to 5 mg / L, and the absolute amount is preferably 0.5 to 8 mg. Examples of vitamin B1 (thiamine) that can be used include thiamine hydrochloride, thiamine nitrate, prosultiamine, and octotiamine.

[0021] <Electrolytes> (a) Potassium Potassium is preferably added separately to the second chamber infusion solution and the first chamber infusion solution. The respective potassium concentrations are preferably 10 to 20 mEq / L in the second chamber infusion solution and 20 to 40 mEq / L in the first chamber infusion solution. A total of 5 to 30 mEq of potassium is preferably added to the first and second chamber infusion solutions.

[0022] The potassium source to be added to the second chamber infusion solution is preferably a strong electrolyte such as potassium chloride or potassium sulfate, with potassium chloride being particularly preferred due to its widespread use. On the other hand, the potassium source to be added to the first chamber infusion solution can be the same as compounds used in general electrolyte infusions, such as potassium chloride, potassium acetate, potassium citrate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium glycerophosphate, potassium sulfate, and potassium lactate. Among these, phosphates such as potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and potassium glycerophosphate are preferred because they also serve as phosphorus sources. These potassium sources may be in the form of hydrates.

[0023] (b) Calcium Calcium is preferably added only to the second chamber infusion solution. This is because adding calcium to the first chamber infusion solution would react with phosphate to form precipitates, and this is prevented by separating calcium from the first chamber infusion solution. Calcium chloride, a strong electrolyte, is preferably used as the calcium source. Furthermore, calcium is preferably present at a concentration of 2 to 10 mEq / L in the second chamber infusion solution.

[0024] (c) Sodium Sodium can be added to either or both of the first and second chamber fluids. However, since it is preferable to use chlorides for potassium and calcium, it is preferable not to use sodium chloride as a sodium source in order to avoid the development of hyperchloremic acidosis.

[0025] When using sodium salts with buffering properties such as sodium acetate, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium lactate, it is preferable to add them to the infusion solution in the first compartment in order to satisfy the above-mentioned titratable acidity requirement of the infusion solution in the second compartment. The compounding concentration in the infusion solution in the first compartment is preferably 80 to 150 mEq / L.

[0026] In order to prevent precipitation of phosphorus with calcium or magnesium after mixing, it is preferable to use sodium citrate as part of the sodium supply source.

[0027] (d) Other Electrolytes (i) Examples of magnesium sources include magnesium sulfate, magnesium chloride, magnesium acetate, etc. Of these, magnesium sulfate and magnesium chloride can be added to the second chamber infusion solution as strong electrolytes. (ii) Examples of phosphorus sources include potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium glycerophosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium glycerophosphate, etc. These phosphorus compounds are added to the first chamber infusion solution. (iii) Examples of zinc sources include zinc sulfate, zinc chloride, etc. These zinc compounds can be added to the second chamber infusion solution.

[0028] Hydrates can be used as the source of each of these electrolytes (i) to (iii), but electrolytes with buffering properties must be added to the infusion solution in the first compartment. Furthermore, the concentrations of each electrolyte are preferably about 2 to 10 mEq / L for magnesium and about 2 to 10 mmol / L for zinc in the infusion solution in the second compartment. Furthermore, it is preferable that the concentration of phosphorus in the infusion solution in the first compartment be about 10 to 20 mmol / L.

[0029] Additives, Compounding Agents Additives such as stabilizers can be added to the infusion preparation of the present invention as needed, and sulfites such as sodium bisulfite, which are representative stabilizers, are preferably added to the infusion solution in the first compartment. In addition, other compounding agents, such as various vitamins and trace elements (minerals), can also be added to the infusion preparation of the present invention as needed.

[0030] <Organic Acid> The organic acid is not particularly limited and can be selected from a wide range of organic acids that can be used as components in infusion preparations, as long as the effects of the present invention are achieved. The organic acid may be used alone or in combination of two or more types.

[0031] The infusion preparation of the present invention is characterized in that the mixed solution contains organic acids in a total amount of 3 mEq / L or more. Preferably, the mixed solution of the infusion preparation of the present invention further contains, in addition to the organic acids contained in the electrolytes, organic acids that are the same as and / or different from the organic acids contained in the electrolytes, in a total amount of 3 mEq / L or more.

[0032] Examples of organic acids include organic acids having a carboxy group.

[0033] Further specific examples of organic acids include hydroxycarboxylic acids and acetic acid. Examples of hydroxycarboxylic acids include gluconic acid, citric acid, lactic acid, succinic acid, tartaric acid, and malic acid. As organic acids, gluconic acid and / or citric acid are particularly preferred in terms of their precipitation-inhibiting effect.

[0034] The mixed solution preferably contains at least one selected from citric acid, lactic acid, and acetic acid in a total amount of 55 mEq / L or more, or contains other organic acids in a total amount of 3 mEq / L or more.

[0035] The pH of the mixed solution from which a total of 3 mEq / L or more of organic acids has been removed is preferably 6.7 or higher, and more preferably 6.75 or higher.

[0036] <Mixture> The sugar concentration in the mixture is desirably set to a range of 50 to 100 g / L, preferably 50 to 90 g / L. The vitamin B1 concentration in the mixture is desirably set to a range of 0.5 to 8 mg / L as thiamine. A suitable example of the amino acid concentrations in the mixture is as follows: In terms of free amino acids, L-leucine: 2.5 to 20 g / L, L-isoleucine: 1.5 to 15 g / L, L-valine: 1.5 to 15 g / L, L-lysine: 1.5 to 15 g / L, L-threonine: 0.6 to 10 g / L, L-tryptophan: 0.15 to 5 g / L, L-methionine: 0.3 to 8 g / L, L-phenylalanine: 0.85 to 15 g / L, L-cysteine: 0. The mixture contains the following components: potassium: 0.03-3 g / L, L-tyrosine: 0.03-2 g / L, L-arginine: 1.5-15 g / L, L-histidine: 0.6-10 g / L, L-alanine: 1.5-15 g / L, L-proline: 0.6-10 g / L, L-serine: 0.3-7 g / L, glycine: 0.6-10 g / L, L-aspartic acid: 0.06-3 g / L, and L-glutamic acid: 0.06-3 g / L. The potassium concentration in the mixture is preferably set to satisfy the range of 5-30 mEq / L. The potassium concentration in the mixture is preferably 16 mEq / L or higher. The calcium concentration in the mixture is preferably set to satisfy the range of 2-8 mEq / L. The calcium concentration in the mixture is preferably 9 mEq / L or lower. The sodium concentration in the mixed solution is desirably set to satisfy the range of 20 to 50 mEq / L, preferably (30 to 50) mEq / L. The magnesium concentration in the mixed solution is desirably set to satisfy the range of 0.5 to 10 mEq / L, preferably 1 to 7 mEq / L. The phosphorus concentration in the mixed solution is desirably set to satisfy the range of 1 to 20 mmol / L, preferably 5 to 10 mEq / L. The zinc concentration in the mixed solution is desirably set to satisfy the range of 2 to 10 μmol / L.The pH of the mixed solution is preferably 6.0 to 6.4, more preferably 6.1 to 6.3, and even more preferably 6.11 to 6.21. A pH of 6.4 or less makes it more likely that precipitation will not occur even if the compounding changes when the mixed solution is mixed with a calcium ion correction solution. A pH of 6.0 or more makes it more likely that vascular pain caused by peripheral intravenous administration will be alleviated.

[0037] The ratio X / Y, where X (mEq / L) is the calcium ion content in the calcium ion correction solution and Y (mEq / L) is the organic acid content in the mixed solution, is preferably 0.1 to 10.3. The closer the ratio X / Y is to 0, the less likely precipitation will occur due to a change in formulation caused by the addition of the calcium ion correction solution. According to the present disclosure, when the pH of the mixed solution is 6.4 and succinic acid is used as the organic acid, and the organic acid concentration is 3.9 mEq / L, precipitation is suppressed even after the addition of 40 meq / L of calcium ions. Therefore, it can be seen that precipitation due to a change in formulation can be suppressed up to a ratio X / Y range of 10.3 or less.

[0038] <Infusion Container> The container for accommodating an infusion solution in a first chamber and an infusion solution in a second chamber is not particularly limited as long as it has two chambers that can communicate with each other, and examples thereof include two-chamber containers (infusion bags) separated by a communicable partition, such as those in which the partition is formed by an easily peelable seal (Japanese Patent Laid-Open No. 2-4671, Japanese Utility Model Laid-Open No. 5-5138, etc.), those in which the partition is formed by clamping the chambers with a clip (Japanese Patent Laid-Open No. 63-309263, etc.), and those in which various openable communication means are provided in the partition (Japanese Patent Publication No. 63-20550, etc.). Of these, infusion bags in which the partition is formed by an easily peelable seal are preferred because they are suitable for mass production and the communication process is easy. Furthermore, examples of the material for the container include various gas-permeable plastics commonly used for medical containers, etc., such as polyethylene, polypropylene, polyvinyl chloride, cross-linked ethylene-vinyl acetate copolymer, ethylene-α-olefin copolymer, and flexible plastics such as blends and laminates of these polymers.

[0039] The first and second chamber infusion liquids can be filled and stored in the container in accordance with conventional methods, such as filling each chamber with the infusion liquid under an inert gas atmosphere, then sealing the chamber and sterilizing by heating.

[0040] Here, heat sterilization can be performed by known methods such as high-pressure steam sterilization and hot water shower sterilization, and can be performed in an inert gas atmosphere such as carbon dioxide or nitrogen, as needed. Furthermore, the infusion preparation of the present invention does not produce insoluble foreign matter even when subjected to high-pressure steam sterilization at a temperature of 116°C to 121°C.

[0041] Furthermore, in order to reliably prevent deterioration, oxidation, etc. of the infusion liquid in the first compartment and the infusion liquid in the second compartment contained in the container, it is preferable to package the container together with a deoxidizer in an oxygen-barrier outer bag. In particular, when an infusion bag having a partition formed with an easily peelable seal is used as the container, the infusion bag is preferably packaged in a folded state at the easily peelable seal portion, for example, in a state folded in half at the easily peelable seal portion, so that the partition does not open due to external pressure. Furthermore, inert gas filling packaging, etc. can also be used if necessary.

[0042] The oxygen barrier outer bag suitable for the packaging can be made of a variety of commonly used films, sheets, etc. Specific examples include ethylene-vinyl alcohol copolymer, polyvinylidene chloride, polyacrylonitrile, polyvinyl alcohol, polyamide, polyester, aluminum foil, metal-deposited film, etc., or films, sheets, etc. made of a material containing at least one of these.

[0043] Various known oxygen absorbers can be used, such as those containing iron compounds such as iron hydroxide, iron oxide, and iron carbide as the active ingredient, and those using low-molecular-weight phenol and activated carbon. Representative commercially available products include "AGELESS" (manufactured by Mitsubishi Gas Chemical Company, Inc.), "MODULAN" (manufactured by Nippon Kayaku Co., Ltd.), "SECURE" (manufactured by Nippon Soda Co., Ltd.), "TAMOTS" (manufactured by Oji Chemical Co., Ltd.), and "KEEPIT" (manufactured by Drenchy Co., Ltd.).

[0044] <Use of Infusion Preparation> The infusion preparation of the present invention is used for the nutritional management of patients before and after surgery when they are in a state of mild hypoproteinemia or mild malnutrition due to insufficient oral intake, or during invasive procedures. It is particularly suitable for the nutritional management of patients who have difficulty receiving nutrition orally after surgery or due to digestive disorders (preferably, patients undergoing gastrointestinal resection). By administering the infusion preparation of the present invention to a patient for 1 to 14 days, preferably 1 to 3 days, after surgery, the patient's nutritional status can be maintained in a healthy state. The dosage and administration rate can be appropriately determined taking into consideration the symptoms, age, etc. of each patient. In particular, the infusion preparation of the present invention alone can maintain a patient's nutritional status during the above-mentioned administration period.

[0045] The infusion preparation of the present invention is administered via a peripheral vein. That is, the infusion preparation of the present invention is an infusion preparation for peripheral intravenous administration. Usually, when an infusion is administered via a peripheral vein, if the osmotic pressure of the infusion is too high, there is a risk of causing vascular pain or phlebitis. However, the infusion preparation of the present invention does not have this risk, and therefore the effects of the infusion preparation of the present invention can be exhibited when administered via a peripheral vein.

[0046] In particular, when the infusion preparation of the present invention is used to mix the mixed solution with a calcium ion correction solution, it exhibits the effect of being less likely to cause precipitation even when the mixture is changed, and is therefore preferably used for such purposes.

[0047] When the mixed solution is used by mixing with a calcium ion correction solution, the calcium ion correction solution preferably contains 360 to 1000 mEq / L of calcium ions. In this case, if calcium chloride hydrate is included as an ingredient, the calcium ion correction solution preferably contains 0.5 g to 1.5 g, and if calcium gluconate hydrate is included, the calcium ion correction solution preferably contains 0.4 g to 0.9 g. Furthermore, after mixing the calcium ion correction solution with the mixed solution of the present invention, the calcium ion concentration is preferably 1.8 to 40 mEq / L.

[0048] When the mixture is used to mix with a calcium ion correction solution, the infusion preparation of the present invention preferably shows no precipitation for 0.5 hours after mixing, more preferably shows no precipitation for 1 hour after mixing, even more preferably shows no precipitation for 3 hours after mixing, even more preferably shows no precipitation for 6 hours after mixing, even more preferably shows no precipitation for 15 hours after mixing, and most preferably shows no precipitation for 24 hours after mixing. In the present invention, the presence or absence of precipitation can be confirmed visually.

[0049] The present invention will be specifically described below, but the present invention is not limited to the following examples.

[0050] Table 1 shows the composition of the infusion solution in the first compartment before adding any acid. Table 2 shows the composition of the infusion solution in the second compartment before adding any acid. Table 3 shows the composition after mixing the infusion solution in the first compartment and the infusion solution in the second compartment. Various infusion preparations were prepared by adding appropriate organic acids as shown in Tables 4 to 8 to the two-liquid mixed infusion preparations of the composition in Table 3. Note that Tables 4 to 8 only show the electrolytes and organic acids of the compositions. Tables 4 to 8 also show the pH of each solution and the mixed solution.

[0051]

[0052]

[0053] The effects of adding calcium chloride correction solution to a mixed solution on compatibility were tested as follows. Specifically, assuming the addition of one ampule (20 mL) of 1 mEq / mL calcium chloride correction solution to 500 mL of mixed solution, this was scaled down and tested in test tubes as follows: (1) 150 mL of infusion solution for the first compartment and 350 mL of infusion solution for the second compartment were measured using a measuring cylinder and mixed in a beaker. (2) With a pH meter (DKK-TOA Corporation, model number: HM-30R) inserted, several μL of organic acid were added to the solution in (1). The organic acid was added until the pH of the mixed solution reached 6.7. (3) Transferred to a 20 mL test tube. (4) Add organic acid to adjust the pH so that it was 0.1 lower than the pH of the previous step (3), and then return to step (3). (5) Repeat steps (3) and (4) until the mixture in the beaker reaches pH 6.0, and prepare test tubes containing 20 mL of each mixture, from pH 6.7 to pH 6.0. (5) Add 0.8 mL of 1 mEq / L calcium chloride correction solution from the top to each test tube containing 20 mL of liquid. Then mix by pipetting 5 mL three times. (6) Cover with parafilm to prevent the liquid from evaporating. (7) Observe over time. If the mixture is "colorless and transparent," mark it with "O," and if it is "white and cloudy," mark it with "X."

[0054] The results are shown below. As comparative examples, examples in which hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid were added instead of organic acids are also shown (Tables 9 to 17).

[0055]

[0056]

[0057]

[0058]

[0059]

[0060] As shown in Tables 9 to 17, when pH was adjusted with various organic acids, precipitate formation was suppressed after a certain period of time following formulation changes with the addition of calcium chloride correction solution, compared with when pH was adjusted with inorganic acids. The degree of precipitation suppression effect after formulation changes at the same pH was generally highest for phosphoric acid, followed by sulfuric acid, nitric acid, hydrochloric acid, acetic acid, succinic acid, lactic acid, and citric acid or gluconic acid (citric acid and gluconic acid were almost equivalent).

Claims

1. An infusion preparation for peripheral intravenous administration having two compartments separated by a communicable partition, the first compartment containing a first compartment infusion solution containing an amino acid, and the second compartment containing a second compartment infusion solution containing a sugar, wherein the mixture of the first compartment infusion solution and the second compartment infusion solution: (A) has a pH of 6.4 or less; and (B) contains a total amount of organic acids of 3 mEq / L or more.

2. The infusion preparation for peripheral intravenous administration according to claim 1, wherein the organic acid has a carboxy group.

3. An infusion preparation for peripheral intravenous administration according to claim 1 or 2, wherein the organic acid is a hydroxycarboxylic acid or acetic acid.

4. An infusion preparation for peripheral intravenous administration according to claim 1 or 2, wherein the pH of the mixture is 6.0 to 6.

4.

5. An infusion preparation for peripheral intravenous administration according to claim 1 or 2, wherein the mixture contains at least one selected from citric acid, lactic acid and acetic acid in a total amount of 55 mEq / L or more, or contains other organic acids in a total amount of 3 mEq / L or more.

6. An infusion preparation for peripheral intravenous administration according to claim 1 or 2, wherein the organic acid is gluconic acid and / or citric acid.

7. An infusion preparation for peripheral intravenous administration according to claim 1 or 2, wherein the mixed solution from which the organic acids have been removed in a total amount of 3 mEq / L or more has a pH of 6.7 or higher.

8. An infusion preparation for peripheral intravenous administration according to claim 1 or 2, wherein the pH of the first chamber infusion is 6.55 or less.

9. A mixture of the first and second compartment infusion liquids according to claim 1 or 2, obtained by partition communication.

10. An infusion preparation for peripheral intravenous administration according to claim 1 or 2, wherein the mixed solution is used to be mixed with a calcium ion correction solution.

11. The infusion preparation for peripheral intravenous administration according to claim 10, wherein the ratio X / Y of the calcium ion content X (mEq / L) in the calcium ion correction solution to the organic acid content Y (mEq / L) in the mixed solution is 0.1 to 10.

3.

12. A method for producing an infusion preparation for peripheral intravenous administration, which has two compartments separated by a communicable partition, the first compartment containing a first compartment infusion solution containing an amino acid, and the second compartment containing a second compartment infusion solution containing a sugar, wherein a mixture of the first compartment infusion solution and the second compartment infusion solution: (A) has a pH of 6.4 or less; and (B) contains a total amount of organic acids of 3 mEq / L or more, the method comprising the step of changing the composition of the first compartment infusion solution and / or the second compartment infusion solution so that the pH of the mixture is 6.4 or less by adding a total amount of organic acids of 3 mEq / L or more to the first compartment infusion solution and / or the second compartment infusion solution so that the pH of the mixture is 6.7 or more.

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