Infusion formulations and methods of making the same

Abstract

The present invention provides a dual-chamber type infusion preparation less likely to form a precipitate even when a composition change is caused by the addition of a calcium ion correction solution. An infusion preparation for peripheral vein administration is provided, which includes two chambers separated by a separator configured to allow fluid communication between the two chambers, the two chambers including a first chamber containing a first chamber infusion solution containing an amino acid and a second chamber containing a second chamber infusion solution containing a sugar, wherein a mixed solution of the first chamber infusion solution and the second chamber infusion solution: (A) has a pH of 6.4 or lower, and (B) contains a total amount of 3 mEq / L or more of an organic acid.

Description

Technical Field

[0001] This invention relates to a two-chamber infusion preparation containing at least amino acids and sugars, the mixture of which is intended to be further mixed with a calcium correction solution, and to a method for manufacturing the two-chamber infusion preparation. Background Technology

[0002] When a corrective solution with a specific electrolyte composition is required, depending on the individual's situation, the electrolyte corrective solution can be mixed with other infusion preparations as needed to allow for the administration of an appropriate infusion solution (PTL 1).

[0003] It has been reported that mixing Ca correction solutions, Mg correction solutions, etc., with other formulations may cause changes in composition and lead to precipitation, so caution is required.

[0004] List of cited references Patent documents PTL 1: JP2011-153083A Summary of the Invention

[0005] Technical issues Many intravenous solutions used for peripheral parenteral nutrition are designed based on the assumption that a corrective solution is added to the electrolyte solution of the infusion. Normally, when the corrective solution is added within the appropriate range, the aforementioned precipitation does not occur, and no problems arise. On the other hand, it is known that when the corrective solution is added to the electrolyte solution while the infusion bag is folded or suspended, adequate mixing is not possible, which may lead to precipitation and cause problems.

[0006] The purpose of this invention is to provide a dual-chamber infusion formulation that is less likely to form a precipitate even when compositional changes are caused by the addition of calcium ion correction solution.

[0007] Solution to the problem The inventors conducted independent research and found that when mixed with calcium ion correction solution, dual-chamber infusion formulations in which the mixed solution is adjusted to pH 6.4 or lower and contains a total amount of organic acids of 3 mEq / L or higher are less likely to form precipitates.

[0008] Specifically, the present invention is made through further improvements and includes the embodiments described in the following items.

[0009] Item 1. An infusion preparation for peripheral intravenous administration, comprising: Two chambers separated by a partition, the partition being configured to allow fluid communication between the two chambers, the two chambers comprising: The first chamber contains a first-chamber infusion solution containing amino acids; and The second chamber contains a second chamber infusion solution containing sugar. The mixture of the infusion fluid from the first chamber and the infusion fluid from the second chamber: (A) pH is 6.4 or lower; and (B) Contains organic acids in a total amount of 3 mEq / L or more.

[0010] Item 2. The infusion preparation for peripheral intravenous administration according to claim 1, wherein the organic acid has a carboxyl group.

[0011] Item 3. The infusion preparation for peripheral intravenous administration according to claim 1 or 2, wherein the organic acid is a hydroxycarboxylic acid or acetic acid.

[0012] Item 4. An infusion preparation for peripheral intravenous administration according to any one of claims 1 to 3, wherein the pH of the mixed solution is 6.0 to 6.4.

[0013] Item 5. An infusion preparation for peripheral intravenous administration according to any one of claims 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 contains one or more other organic acids in a total amount of 3 mEq / L or more.

[0014] Item 6. An infusion preparation for peripheral intravenous administration according to any one of claims 1 to 5, wherein the organic acid is gluconic acid and / or citric acid.

[0015] Item 7. An infusion preparation for peripheral intravenous administration according to any one of claims 1 to 6, wherein the pH of the liquid obtained by removing a total amount of organic acid of 3 mEq / L or more from the mixed solution is 6.7 or higher.

[0016] Item 8. An infusion preparation for peripheral intravenous administration according to any one of claims 1 to 7, wherein the pH of the infusion solution in the first chamber is 6.55 or lower.

[0017] Item 9. A mixed solution, which is a mixture of a first chamber infusion fluid and a second chamber infusion fluid as described in any one of claims 1 to 8, obtained by allowing fluid communication via a separator.

[0018] Item 10. An infusion preparation for peripheral intravenous administration according to any one of claims 1 to 8, used for mixing a mixed solution with a calcium ion correction solution.

[0019] Item 11. According to item 10, 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 from 0.1 to 10.3.

[0020] Item 12. A method for manufacturing an infusion formulation for peripheral intravenous administration. Infusion formulations for peripheral intravenous administration include two chambers separated by a separator, the separator being configured to allow fluid communication between the two chambers, the two chambers comprising: The first chamber contains a first chamber infusion solution containing amino acids; and The second chamber contains a second chamber infusion solution containing sugar. The mixture of the infusion fluid from the first chamber and the infusion fluid from the second chamber: (A) pH is 6.4 or lower; and (B) Contains organic acids in a total amount of 3 mEq / L or more. The above methods include: An organic acid in a total amount of 3 mEq / L or more is added to the first chamber infusion solution and / or the second chamber infusion solution, wherein the pH of the mixture of the first chamber infusion solution and the second chamber infusion solution is 6.7 or higher before the addition, thereby changing the composition of the first chamber infusion solution and / or the second chamber infusion solution such that the pH of the mixture is 6.4 or lower.

[0021] Beneficial effects of the present invention The infusion formulation of the present invention has the following effect: it can inhibit precipitation even when the composition changes when the mixed solution is mixed with calcium ion correction solution. Detailed Implementation

[0022] The present invention will now be described in more detail.

[0023] The present invention relates to an infusion preparation comprising two chambers separated by a partition configured to allow fluid communication between the two chambers, the two chambers including a first chamber containing a first chamber infusion solution containing amino acids, and a second chamber containing a second chamber infusion solution containing sugars.

[0024] In the infusion formulation of the present invention, the mixed solution of the first chamber infusion solution and the second chamber infusion solution is as follows: (A) pH is 6.4 or lower; and (B) Contains organic acids in a total amount of 3 mEq / L or more. Due to this characteristic, the infusion formulation of the present invention has the following effect: precipitation can be suppressed even when the composition changes when the mixed solution is mixed with calcium ion correction solution.

[0025] Infusion in the first chamber The first-compartment infusion solution used in this invention contains amino acids. The first-compartment infusion solution contains an amino acid composition comprising at least one essential amino acid. The amino acid is contained at a concentration of 50 to 150 g / L, preferably 80 to 120 g / L, based on free amino acids. Each amino acid used is preferably a pure crystalline amino acid, as in general amino acid infusion solutions. Although these amino acids are generally used in the form of free amino acids, they are not necessarily limited to the free amino acid form and may also be used in the form of pharmacologically acceptable salts, esters, N-acyl derivatives, salts of two amino acids, or peptides. In particular, from a stability perspective, L-cysteine ​​is preferably incorporated in the form of an N-acetyl derivative. The fluid volume of the first-compartment infusion solution to be contained in the infusion container is preferably 100 to 500 mL. The solvent used for the first-compartment infusion solution is generally distilled water for injection.

[0026] Preferred amino acid compositions may include (based on free amino acids): 5 to 20 g / L L-leucine, 3 to 15 g / L L-isoleucine, 3 to 15 g / L L-valine, 3 to 15 g / L L-lysine, 1.2 to 10 g / L L-threonine, 0.3 to 5 g / L L-tryptophan, 0.6 to 8 g / L L-methionine, 1.8 to 15 g / L L-phenylalanine, 0.1 to 3 g / L L-lysine, and 0.5 to 10 g / L L-threonine. L-cysteine ​​(0.06 to 2 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), and L-glutamic acid (0.12 to 3 g / L).

[0027] If necessary, the pH of the first chamber infusion solution can be adjusted to 6.57 or lower, preferably 6.57 to 6.06, and more preferably 6.46 to 6.06, by adding a small amount of pH adjuster. The pH adjuster is preferably an organic acid. When the pH is 6.55 or lower, the pH after mixing can be easily maintained within the optimal range described below.

[0028] Second chamber infusion In this invention, the second chamber infusion solution contains sugar. Specifically, for example, the second chamber infusion solution may have basic components including glucose, strong electrolytes, and vitamin B1, and may be free of sulfites to stabilize vitamin B1.

[0029] Glucose is used at a concentration of 80 to 200 g / L, preferably 80 to 150 g / L. In this glucose solution, the concentration of carboxylic acids and their salts is more preferably maintained at 0 to 5 mEq / L from the perspective of stabilizing vitamin B1. To minimize buffering capacity, the pH of the glucose solution is preferably adjusted using an inorganic acid (e.g., hydrochloric acid), and more preferably, all electrolytes contained are strong electrolytes. The pH of the second-chamber infusion solution is in the range of 3 to 5, preferably 3.5 to 4.5. When the pH is below 3, the stability of glucose is insufficient, despite the excellent stability of vitamin B1 itself. On the other hand, when the pH is above 5, vitamin B1 becomes less stable.

[0030] The preferred fluid volume of the glucose solution is 200 to 1000 mL. The solvent for the glucose solution is typically distilled water for injection. To further improve 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 lower, more preferably 0.5 or lower, and even more preferably 0.1 or lower.

[0031] In addition to glucose, one or more reducing sugars (e.g., fructose and maltose) may be added in appropriate amounts, or one or more non-reducing sugars (e.g., sorbitol and glycerol) may be added in appropriate amounts.

[0032] Vitamin B1 Vitamin B1 is preferably added to the second-compartment infusion solution in the form of thiamine at a concentration of 1 to 10 mg / L, preferably 2 to 5 mg / L, and more preferably in an absolute amount of 0.5 to 8 mg. Thiamine hydrochloride, thiamine nitrate, prosultiamine, octotiamine, etc., can be used as vitamin B1.

[0033] electrolytes (a) Potassium Potassium is preferably added in portions to the second chamber infusion solution and the first chamber infusion solution. The concentration of potassium in the second chamber infusion solution is preferably 10 to 20 mEq / L, and the concentration in the first chamber infusion solution is preferably 20 to 40 mEq / L. Potassium is preferably incorporated into both the first and second chamber infusion solutions in a total amount of 5 to 30 mEq.

[0034] The potassium source added to the infusion solution in the second chamber is preferably a strong electrolyte, such as potassium chloride or potassium sulfate. Potassium chloride is particularly preferred because it is widely used. Alternatively, the potassium source added to the infusion solution in the first chamber can be a compound similar to those used in general electrolyte infusion solutions, examples of which include potassium chloride, potassium acetate, potassium citrate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium glycerophosphate, potassium sulfate, and potassium lactate. Among these potassium sources, phosphates (such as potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and potassium glycerophosphate) are preferred because they also serve as phosphorus sources. These potassium sources can be in hydrate form.

[0035] (b) Calcium Preferably, calcium is added only to the second chamber infusion solution. If calcium is added to the first chamber infusion solution, it will react with phosphate to form a precipitate. To avoid this, it is preferable to keep the calcium separate. Preferably, calcium chloride, a strong electrolyte, is used as the calcium source. Calcium is preferably present in the second chamber infusion solution at a concentration of 2 to 10 mEq / L.

[0036] (c) Sodium Sodium can be added to the first chamber infusion solution, the second chamber infusion solution, or both. Since potassium and calcium in chloride form are preferred, sodium chloride is preferably not used as a sodium source to avoid hyperchloremic acidosis.

[0037] When using a buffered sodium salt (e.g., sodium acetate, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, or sodium lactate), sodium is preferably added to the first chamber infusion solution to meet the titratable acidity requirements of the second chamber infusion solution. Sodium is preferably present in the first chamber infusion solution at a concentration of 80 to 150 mEq / L.

[0038] To prevent phosphorus from precipitating with calcium or magnesium after mixing, sodium citrate is preferably used as part of the sodium source.

[0039] (d) Other electrolytes (i) Examples of magnesium sources include magnesium sulfate, magnesium chloride, and magnesium acetate. Among these, magnesium sulfate and magnesium chloride can be added as strong electrolytes to the infusion solution of the second chamber.

[0040] (ii) Examples of phosphorus sources include potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium glycerophosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium glycerophosphate. These phosphorus compounds may be added to the infusion solution in the first chamber.

[0041] (iii) Examples of zinc sources include zinc sulfate and zinc chloride. These zinc compounds can be added to the second-chamber infusion solution.

[0042] Hydrates can also be used as electrolyte sources (i) to (iii); however, buffering electrolytes must be added to the first chamber infusion solution. The concentrations of the various electrolytes are preferably such that the second chamber infusion solution contains about 2 to 10 mEq / L of magnesium and about 2 to 10 mmol / L of zinc, and the first chamber infusion solution contains about 10 to 20 mmol / L of phosphorus.

[0043] Additives and other components Additives (e.g., stabilizers) may be added to the infusion formulations of the present invention as needed. Sulfites (such as sodium bisulfite, a typical stabilizer) may be appropriately added to the first chamber infusion solution. Other reagents (including, for example, various vitamins and trace elements (minerals)) may also be optionally added to the infusion formulations of the present invention as needed.

[0044] organic acids There are no particular limitations on the organic acids used; any organic acid that can be used as a component of an infusion preparation can be broadly selected, as long as it achieves the effects of this invention. These organic acids can be used alone or in combination of two or more.

[0045] The infusion formulation of the present invention is characterized in that the mixed solution contains an organic acid in a total amount of 3 mEq / L or more. Preferably, in the infusion formulation of the present invention, in addition to the organic acid contained in the electrolyte, the mixed solution also contains one or more identical and / or different organic acids in a total amount of 3 mEq / L or more.

[0046] Examples of organic acids include organic acids that have a carboxyl group.

[0047] Other 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. From the perspective of inhibiting precipitation, gluconic acid and / or citric acid are preferred organic acids.

[0048] 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 one or more other organic acids in a total amount of 3 mEq / L or more.

[0049] After removing a total amount of organic acids of 3 mEq / L or more, the pH of the mixed solution is preferably 6.7 or higher, more preferably 6.75 or higher.

[0050] Mixed solution Preferably, the sugar concentration in the mixed solution is set in the range of 50 to 100 g / L, and more preferably 50 to 90 g / L.

[0051] Desiredly, the concentration of vitamin B1 in the mixed solution is set in the range of 0.5 to 8 mg / L, calculated as thiamine.

[0052] Preferred examples of amino acid concentrations in the mixed solution are as follows (based on free amino acids): 2.5 to 20 g / L L-leucine, 1.5 to 15 g / L L-isoleucine, 1.5 to 15 g / L L-valine, 1.5 to 15 g / L L-lysine, 0.6 to 10 g / L L-threonine, 0.15 to 5 g / L L-tryptophan, 0.3 to 8 g / L L-methionine, 0.85 to 15 g / L L-phenylalanine, 0.03 to 3 g / L L-cysteine, 0.03 to 2 g / L L-tyrosine, 1.5 to 15 g / L L-arginine, 0.6 to 10 g / L L-histidine, 1.5 to 15 g / L L-alanine, 0.6 to 10 g / L L-proline, 0.3 to 7 g / L L-lysine, and 0.3 to 7 g / L L-phosphine. L-serine (0.6 to 10 g / L), glycine (0.06 to 3 g / L), L-aspartic acid (0.06 to 3 g / L), and L-glutamic acid (0.06 to 3 g / L).

[0053] Desiredly, the potassium concentration in the mixed solution is set in the range of 5 to 30 mEq / L. Alternatively, desired, the potassium concentration in the mixed solution is 16 mEq / L or higher.

[0054] Desiredly, the calcium concentration in the mixed solution is set in the range of 2 to 8 mEq / L. Alternatively, desired, the calcium concentration in the mixed solution is 9 mEq / L or lower.

[0055] Desiredly, the sodium concentration in the mixed solution is set in the range of 20 to 50 mEq / L, preferably 30 to 50 mEq / L.

[0056] Desiredly, the magnesium concentration in the mixed solution is set in the range of 0.5 to 10 mEq / L, preferably 1 to 7 mEq / L.

[0057] Desiredly, the phosphorus concentration in the mixed solution is set in the range of 1 to 20 mmol / L, preferably 5 to 10 mEq / L.

[0058] Desiredly, the zinc concentration in the mixed solution is set in the range of 2 to 10 μmol / L.

[0059] 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. When the pH is 6.4 or lower, the precipitation-inhibiting effect is more pronounced even when the composition changes upon mixing with the calcium ion correction solution. When the pH is 6.0 or higher, it exhibits a promoting effect in reducing vascular pain during peripheral intravenous administration.

[0060] 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 preferably 0.1 to 10.3. The closer the ratio X / Y is to zero, the less likely precipitation will occur due to compositional changes caused by the addition of the calcium ion correction solution. According to this disclosure, when the pH of the mixed solution is 6.4 and succinic acid is used as the organic acid, and when the organic acid concentration is 3.9 mEq / L, it has been confirmed that precipitation is suppressed even after the addition of 40 mEq / L of calcium ions. This indicates that precipitation caused by compositional changes can be suppressed as long as the ratio X / Y is 10.3 or less.

[0061] Infusion container There are no particular limitations on the containers used to contain infusion fluid in the first and second chambers, as long as the container has two interconnected chambers. Examples include dual-chamber containers (infusion bags) where the chambers are separated by partition walls configured to allow fluid communication between the chambers, such as containers using easily peelable seals as partition walls (Japanese Unexamined Patent Publication No. H2-4671, Japanese Unexamined Utility Model Publication No. H5-5138, etc.); containers where partition walls are formed by clamping the space between the chambers (Japanese Unexamined Patent Publication No. S63-309263, etc.); and containers with various communication devices on the partition walls that allow opening the partition walls (Japanese Patent Examination Publication No. S63-20550, etc.). Among these, infusion bags using easily peelable seals as partition walls are preferred because they are suitable for mass production and the chambers are easily interconnected. Furthermore, various breathable plastics commonly used in medical containers can be used as the container material. Examples include flexible plastics such as polyethylene, polypropylene, polyvinyl chloride, cross-linked ethylene-vinyl acetate copolymers, ethylene-α-olefin copolymers, blends of these polymers, and laminates comprising these polymers.

[0062] The infusion solutions for the first and second chambers can be filled into containers and packaged using conventional methods. For example, the infusion solutions can be filled into the chambers under an inert gas atmosphere, sealed, and then heat-sterilized.

[0063] Heat sterilization can be performed by known methods, such as autoclaving or hot water spray sterilization. If necessary, heat sterilization can be performed under an inert gas atmosphere (such as carbon dioxide or nitrogen). Even when sterilized under autoclaved steam at 116 to 121°C, the infusion formulations of the present invention will not produce undesirable insoluble substances.

[0064] Furthermore, the first and second chamber infusion solutions contained in the container are preferably packaged together with an oxygen barrier exterior bag to reliably prevent deterioration and oxidation. In particular, when using an infusion bag with an easy-release seal as a spacer as the container, it is preferable to package the infusion bag in a manner that folds (e.g., in half) at the easy-release seal portion to prevent the spacer wall from being opened open by external pressure. Additionally, for example, filling and packaging can optionally be carried out under an inert gas atmosphere.

[0065] Common films and sheets made from various materials can be used as materials suitable for oxygen-barrier outer packaging bags. Specific examples include ethylene-vinyl alcohol copolymers, polyvinylidene chloride, polyacrylonitrile, polyvinyl alcohol, polyamide, polyester, aluminum foil, and metallized films, as well as films and sheets made from materials including at least one of these materials.

[0066] Available deoxidizers include a variety of known deoxidizers, such as those containing ferric hydroxide, ferric oxide, ferric carbide, or other iron compounds as active ingredients, and those containing low molecular weight phenols and activated carbon. Examples of typical commercial product names include Ageless (Mitsubishi Gas Chemical Company, Inc.), Moduran (Nippon Kayaku Co., Ltd.), Secure (Nippon Soda Co., Ltd.), Tamotsu (Oji Kako Co., Ltd.), and Keepit (Dorency Co., Ltd.).

[0067] Intravenous preparation usage The infusion preparation of the present invention is used for nutritional management of patients before and after surgery, for patients with mild hypoalbuminemia or mild malnutrition due to insufficient oral intake, or for patients in the postoperative stress period. In particular, the infusion preparation is suitable for nutritional management of patients during the postoperative period or those who have difficulty receiving oral nutritional support due to digestive system diseases (preferably, patients who have undergone gastrectomy). The infusion preparation of the present invention is administered to patients 1 to 14 days postoperatively, preferably 1 to 3 days postoperatively. This allows the patient's nutritional status to be maintained at a healthy level. The dosage and administration rate can be appropriately determined according to each patient's symptoms, age, etc. Specifically, when using the infusion preparation of the present invention, the infusion preparation itself can maintain the patient's nutritional status at a healthy level during the administration period.

[0068] The infusion formulation of the present invention is administered into a peripheral vein. In other words, the infusion formulation of the present invention is an infusion formulation for peripheral intravenous administration. Typically, administering an infusion with excessively high osmotic pressure into a peripheral vein can cause vascular pain or phlebitis. However, such risks do not exist when using the infusion formulation of the present invention. Therefore, when the infusion formulation of the present invention is administered into a peripheral vein, the effects of the infusion formulation of the present invention can be appropriately exerted.

[0069] In particular, the infusion formulation of the present invention has the effect of inhibiting precipitation even when the composition changes when the mixed solution is mixed with calcium ion correction solution. Therefore, the infusion formulation of the present invention is preferably used in such applications.

[0070] When the mixed solution is mixed with the calcium ion correction solution, the calcium ion correction solution preferably contains 360 to 1000 mEq / L of calcium ions. In this case, when hydrated calcium chloride is included as a component, its amount is preferably 0.5 g to 1.5 g; when hydrated calcium gluconate is included as a component, its amount is preferably 0.4 g to 0.9 g. Additionally, it is desirable that after mixing the calcium ion correction solution with the mixed solution of the present invention, the calcium ion concentration is 1.8 to 40 mEq / L.

[0071] When the mixed solution is mixed with the calcium ion correction solution, the infusion formulation of the present invention preferably does not form a precipitate within 0.5 hours after mixing, more preferably within 1 hour after mixing, even more preferably within 3 hours after mixing, even more preferably within 6 hours after mixing, even more preferably within 15 hours after mixing, and most preferably within 24 hours after mixing. In the present invention, the presence of a precipitate can be visually confirmed.

[0072] Example The present invention will now be described in detail; however, the present invention is not limited to the following embodiments.

[0073] Table 1 shows the composition of the first-chamber infusion solution before the addition of acid. Table 2 shows the composition of the second-chamber infusion solution before the addition of acid. Table 3 shows the composition after mixing the first-chamber and second-chamber infusion solutions. Various infusion formulations were prepared using the dual-chamber infusion formulations with the compositions shown in Table 3 as a base, by appropriately adding the organic acids shown in Tables 4 to 8. Tables 4 to 8 only show the electrolytes and organic acids in the components. Tables 4 to 8 also show the pH of the infusion solutions and mixtures.

[0074] [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] The effect of adding calcium chloride correction solution on the compositional change of the mixed solution was tested as follows. Specifically, a case was presented in which a single ampoule (20 mL) of 1 mEq / mL calcium chloride correction solution was added to 500 mL of the mixed solution. This process was scaled down as described below and tested in test tubes.

[0075] (1) Use a graduated cylinder to measure 150 mL of the first chamber infusion solution and 350 mL of the second chamber infusion solution, and mix them together in a beaker.

[0076] (2) While inserting the pH meter (model: HM-30R, DKK-TOA Corporation), add a few microliters of organic acid to the solution in (1). The pH of the mixed solution is 6.7 when the organic acid is added.

[0077] (3) Transfer the resulting mixed solution to a 20 mL test tube.

[0078] (4) Add organic acid to reduce the pH by 0.1 from the pH obtained in step (3) and return to the operation of step (3).

[0079] (5) Repeat steps (3) to (4) until the pH of the mixed solution in the beaker reaches 6.0, thus preparing test tubes, each containing 20 mL of mixed solution with a pH of 6.7 to 6.0.

[0080] (6) Add 0.8 mL of 1 mEq / L calcium chloride correction solution to the surface of each test tube containing 20 mL of solution. Then mix the mixture by pipetting 5 mL of the mixed solution three times.

[0081] (7) Seal each test tube with Parafilm to prevent the solution from evaporating.

[0082] (8) Observe the changes over time and evaluate the results as follows: “〇”: colorless and transparent; “×”: white and turbid.

[0083] The results are shown below. Comparative examples of adding hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid in place of organic acids are also shown (Tables 9 to 17).

[0084] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] As shown in Tables 9 to 17, compared to the case where pH was adjusted using inorganic acids, precipitation caused by compositional changes when calcium chloride correction solution was added was inhibited over a specific time period when pH was adjusted using various organic acids. At the same pH, the largest effects of inhibiting precipitation after compositional changes were observed in the following order from largest to smallest: phosphoric acid, sulfuric acid, nitric acid, hydrochloric acid, acetic acid, succinic acid, lactic acid, and citric acid or gluconic acid (citric acid and gluconic acid showed substantially the same degree of effect).

Claims

1. An infusion preparation for peripheral intravenous administration, comprising: Two chambers separated by a partition, the partition being configured to allow fluid communication between the two chambers, the two chambers comprising: A first chamber containing an infusion solution containing amino acids; and a second chamber containing an infusion solution containing sugars. The mixture of the first chamber infusion fluid and the second chamber infusion fluid is as follows: (A) pH is 6.4 or lower; and (B) Contains organic acids in a total amount of 3 mEq / L or more.

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

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

4. The infusion formulation for peripheral intravenous administration according to claim 1 or 2, wherein the pH of the mixed solution is 6.0 to 6.

4.

5. The infusion formulation for peripheral intravenous administration according to claim 1 or 2, 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 contains one or more other organic acids in a total amount of 3 mEq / L or more.

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

7. The infusion formulation for peripheral intravenous administration according to claim 1 or 2, wherein the pH of the liquid after removing a total amount of organic acid of 3 mEq / L or more from the mixed solution is 6.7 or higher.

8. The infusion formulation for peripheral intravenous administration according to claim 1 or 2, wherein the pH of the first chamber infusion solution is 6.55 or lower.

9. A mixed solution, which is a mixture of a first chamber infusion fluid and a second chamber infusion fluid as described in claim 1 or 2, obtained by allowing fluid communication via a separator.

10. The infusion formulation for peripheral intravenous administration according to claim 1 or 2, wherein the mixed solution is 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 from 0.1 to 10.

3.

12. A method for manufacturing an infusion formulation for peripheral intravenous administration, The infusion formulation for peripheral intravenous administration includes two chambers separated by a separator, the separator being configured to allow fluid communication between the two chambers, the two chambers comprising: The first chamber contains a first chamber infusion solution containing amino acids; and The second chamber contains a second chamber infusion solution containing sugar. The mixture of the first chamber infusion fluid and the second chamber infusion fluid is as follows: (A) pH 6.4 or lower; and (B) Contains organic acids in a total amount of 3 mEq / L or more. The method includes: An organic acid in a total amount of 3 mEq / L or more is added to the first chamber infusion solution and / or the second chamber infusion solution, wherein the pH of the mixture of the first chamber infusion solution and the second chamber infusion solution is 6.7 or higher before addition, thereby changing the composition of the first chamber infusion solution and / or the second chamber infusion solution such that the pH of the mixture is 6.4 or lower.

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