TRANSFUSION PREPARATION

Abstract

The present invention provides an infusion preparation that is inhibited from generation of unwanted insoluble matter after mixing of two liquids of the infusion preparation in long-term storage. More specifically, the present invention provides an infusion preparation comprising two chambers separated by a communicably openable partition, a first chamber containing a first-chamber infusion comprising a fat emulsion and further comprising at least one member selected from the group consisting of amino acids that have a buffer action, divalent organic acids, and trivalent organic acids, a second chamber containing a second-chamber infusion comprising an amino acid and at least calcium as an electrolyte, wherein a total concentration of the amino acids that have a buffer action, divalent organic acids, and trivalent organic acids in the first-chamber infusion is 0.15 to 0.5 g/L, and a mixture of the first- and second-chamber infusions has a pH of 6.53 or less as measured 48 hours after the partition is communicably opened.

Claims

1. An infusion preparation comprising two chambers separated by a communicably openable partition, a first chamber containing a first-chamber infusion comprising a fat emulsion and further comprising at least one member selected from the group consisting of amino acids that have a buffer action, divalent organic acids, and trivalent organic acids, a second chamber containing a second-chamber infusion comprising an amino acid and at least calcium as an electrolyte, wherein a total concentration of the amino acids that have a buffer action, divalent organic acids, and trivalent organic acids in the first-chamber infusion is 0.15 to 0.5 g/L, and a mixture of the first- and second-chamber infusions has a pH of 6.53 or less as measured 48 hours after the partition is communicably opened.

2. The infusion preparation according to claim 1, wherein the fat emulsion comprises an emulsifying agent, and the first-chamber infusion comprises the emulsifying agent in a concentration of 0.01 to 2 w/v %.

3. The infusion preparation according to claim 1, wherein the mixture of the first- and second-chamber infusions after the partition is communicably opened contains Ca.sup.2+ in a concentration of 1 mEq/L or more.

4. The infusion preparation according to claim 1, wherein the second-chamber infusion further comprises at least citric acid as the electrolyte, and the second-chamber infusion has a citric acid concentration (mEq) equal to or more than the calcium concentration (mEq).

5. The infusion preparation according to claim 1, wherein the first-chamber infusion comprises at least histidine as the amino acids that have a buffer action.

6. A mixture of the first- and second-chamber infusions of claim 1 obtained by communicably opening the partition.

Description

EXAMPLES

[0136] The present invention is described in more detail below with reference to Examples. The invention, however, is not limited to the following Examples.

Production of Infusion Preparations

1. Production of First-Chamber Infusions 1 to 4

[0137] Purified soybean oil, purified egg yolk lecithin, and glucose in the amounts shown in Table 2 were added to water. The resulting mixture was subjected to crude emulsification using a homomixer. The resulting crude emulsion was then subjected to fine emulsification using a high-pressure emulsifier (Manton-Gaulin). Further, L-histidine in the amounts shown in Table 2 and water were added thereto to make the total volume of each emulsion 300 mL. Further, hydrochloric acid was used to adjust the pH. The first-chamber infusions thus obtained had a relative osmotic pressure of 2.9 and a titratable acidity of 1.

TABLE-US-00002 TABLE 2 Formulation Formulation Formulation Formulation 1 2 3 4 Purifled 10 g soybean oil Glucose 37.5 g Purified egg 1.2 g yolk lecithin L-histidine 0.03 g 0.06 g 0.09 g 0.15 g pH 6.3 6.3 6.3 6.3

2. Formulation of Second-Chamber Infusions A to D

[0138] Amino acids, electrolytes, and a stabilizer (sodium hydrogen sulfite) in the amounts shown in Table 3 were dissolved in distilled water for injection to prepare an amino acid electrolyte solution. Further, the pH of the electrolyte solution was adjusted to the levels shown in Table 3 with glacial acetic acid, and the total volume of each solution was adjusted to 250 mL, giving second-chamber infusions. The second-chamber infusions thus obtained had a relative osmotic pressure of 2.7. The second-chamber infusions had a citric acid concentration of 12.68 mEq/L and a calcium concentration of 10.00 mEq/L.

TABLE-US-00003 TABLE 3 Formu- Formu- Formu- lation A lation B lation C L-leucine 2.100 g L-isoleucine 1.200 g L-valine 1.200 g L-lysine hydrochloride 1.965 g L-threonine 0.855 g L-tryptophan 0.300 g L-methionine 0.585 g Acetylcysteine 0.202 g L-phenylalanine 1.050 g L-tyrosine 0.075 g L-arginine 1.575 g L-histidine 0.750 g L-alanine 1.200 g L-proline 0.750 g L-serine 0.450 g Glycine 0.885 g L-aspartic acid 0.150 g L-glutamic acid 0.150 g Sodium chloride 0.215 g Potassium chloride 0.220 g Sodium citrate hydrate 0.311 g Sodium L-lactate 1.967 g solution (60%) (1.180 g) (as sodium L-lactate) 50% potassium 1.750 g glycerophosphate (0.875 g) solution (as potassium glycerophosphate) Calcium gluconate hydrate 0.561 g Magnesium sulfate hydrate 0.309 g Zinc sulfate hydrate 0.72 mg Sodium bisulfite 12.5 mg pH 6.5 6.7 6.9

3. Filling and Packaging

[0139] Using two-chamber polyethylene containers with the chambers being partitioned by an easily peelable seal, formulations 1 to 4 were placed as the first-chamber infusion in the lower chambers of the containers, whereas formulations A to C were placed as the second-chamber infusion in the upper chambers of the containers. After the atmosphere in the vacant space of each chamber was replaced with nitrogen gas and each container was sealed, high-pressure steam sterilization was performed at a temperature of 116 C. for 26 minutes. Each container was then folded at the easily peelable seal portion, and enclosed with a deoxidant in an exterior bag made of gas barrier film, thus obtaining an infusion preparation. Three preparations of the same infusion were prepared for each type.

[0140] The infusion preparations obtained above, containing formulations 1 to 4 as the first-chamber infusion and formulation A as the second-chamber infusion, were stored at 60 C./75% RH for 3 weeks, and then the first-chamber infusion and second-chamber infusion were mixed. Whether unwanted insoluble matter was generated was confirmed immediately after mixing, 26 hours after mixing, and 48 hours after mixing. The pH was measured 48 hours after mixing. Table 4 shows the results.

[0141] Whether free fatty acids were formed was visually evaluated according to the following criteria. [0142] A: No unwanted insoluble matter was observed on the inner surface of the container. [0143] B: White unwanted insoluble matter was observed on the inner surface of the container.

TABLE-US-00004 TABLE 4 Confirmation on Lower generation of unwanted Upper chamber: insoluble matter chamber: first-chamber Measurement time second- infusion Imme- 26 48 chamber (amount of Round diately hours hours infusion L-histidine of after after after (pH) added) tests mixing mixing mixing pH Formulation Formulation 1 1st A B B 6.40 A (0.1 g/L) 2nd A B B 6.39 (pH 6.5) 3rd A B B 6.40 Formulation 2 1st A A A 6.41 (0.2 g/L) 2nd A A A 6.40 3rd A A A 6.41 Formulation 3 1st A A A 6.39 (03 g/L) 2nd A A A 6.40 3rd A A A 6.39 Formulation 4 1st A A A 6.37 (0.5 g/L) 2nd A A A 6.37 3rd A A A 6.38

[0144] When the infusion preparation comprised formulation 1 containing L-histidine in a concentration of 0.1 g/L as the first-chamber infusion/white unwanted insoluble matter started to be observed on the inner surface of the containers containing the preparation 26 hours after mixing.

[0145] The infusion preparations obtained above, each containing one of formulations 1 to 4 as the first-chamber infusion and containing formulation B as the second-chamber infusion, were stored at 60 C./75% RH for 3 weeks, and then the first-chamber infusion and the second-chamber infusion were mixed. Whether unwanted insoluble matter was generated was confirmed immediately after mixing, 26 hours after mixing, and 48 hours after mixing. The pH was measured 48 hours after mixing. Table 5 shows the results.

[0146] Whether free fatty acids were formed was confirmed in the same manner as described above.

TABLE-US-00005 TABLE 5 Confirmation on Lower generation of unwanted Upper chamber insoluble matter chamber: first-chamber Measurement time second- infusion Imme- 26 48 chamber (amount of Round diately hours hours infusion L-histidine of after after after (pH) added) tests mixing mixing mixing pH Formulation Formulation 1 1st A B B 6.53 B 0.03 g/L) 2nd A B B 6.53 (pH 6.7) 3rd A B 8 6.53 Formulation 2 1st A B B 6.54 0.03 g/L) 2nd A B B 6.55 3rd A B B 6.54 Formulation 3 1st A A A 6.53 0.03 g/L) 2nd A A A 6.53 3rd A A A 6.53 Formulation 4 1st A A A 6.51 (0.03 g/L) 2nd A A A 6.52 3rd A A A 6.52

[0147] When the infusion preparation comprised formulation 1 containing L-histidine in a concentration of 0.1 g/L as the first-chamber infusion, white unwanted insoluble matter started to be observed on the inner surface of the containers containing the preparation 26 hours after mixing. Further, when the infusion preparation comprised formulation 2 and formulation B and had a pH of 6.54 or 6.55 after mixing, white unwanted insoluble matter started to be observed on the inner surface of the containers containing the mixture of formulation 2 and formulation B 26 hours after mixing.

[0148] The infusion preparations obtained above, each containing one or formulations 1 to 4 as the first-chamber infusion and formulation C as the second-chamber infusion, were stored at 60 C./75% RH for 3 weeks, and then the first-chamber infusion and the second-chamber infusion were mixed. Whether unwanted insoluble matter was generated was confirmed immediately after mixing, 26 hours after mixing, and 43 hours after mixing. The pH was measured 48 hours after mixing. Table 6 shows the results.

[0149] Whether free fatty acids were formed was confirmed in the same, manner as described above.

TABLE-US-00006 TABLE 6 Confirmation on Lower generation of unwanted Upper chamber insoluble matter chamber: first-chamber Measurement time second- infusion Imme- 26 48 chamber (amount of L- Round diately hours hours infusion histidine of after after after (pH) added) tests mixing mixing mixing pH Formulation Formulation 1 1st A B B 6.66 C (0.03 g/ 2nd A B B 6.68 (pH 6.9) 300 mL) 3rd A B B 6.68 Formulation 2 1st A B B 6.67 (0.06 g/ 2nd A B B 6.68 300 mL) 3rd A B B 6.68 Formulation 3 1st A B B 6.68 (0.09 g/ 2nd A B B 6.68 300 mL) 3rd A B B 6.68 Formulation 4 1st A B B 6.65 (0.15 g/ 2nd A B B 6.65 300 mL) 3rd A B B 6.65

[0150] Forty-eight hours after mixing, all of the infusion preparations containing formulation C having a pH of 6.9 as the second-chamber infusion had a pH higher than 6.53, no matter which of formulations 1 to 4 was used as the first-chamber infusion. Further, white unwanted insoluble matter started to be observed on the inner surface of the containers 26 hours after mixing.