JP2003095937A - Peripheral intravenous transfusion - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a peripheral intravenous transfusion with which angiopathy is reduced. SOLUTION: This peripheral intravenous transfusion is added or formulated with >=15 mEq/L citrate as citrate ions.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an infusion solution for peripheral veins.

[0002]

2. Description of the Related Art The most frequent and problematic side effects of peripheral vein infusion are vascular pain and phlebitis. In particular, in the case of electrolyte transfusions containing sugars such as glucose and fructose, the pH must be lowered to prevent discoloration during sterilization, which may cause vascular pain and phlebitis. Further, it is said that an infusion solution having an osmotic pressure higher than that of plasma causes vascular pain and phlebitis due to hypertonicity. Furthermore, it is said that hypertonic and low pH infusions are prone to vascular pain and phlebitis due to both causes. Therefore, it is desired to develop a safer peripheral vein infusion that reduces the occurrence of vascular pain and phlebitis without lowering the effects (quantity and quality) of water / electrolyte supplementation and nutrition supplementation, which are the purpose of infusion. It was In JP-A-59-16818, citric acid is added to an infusion solution containing glucose and an electrolyte, the purpose of which is to prevent caramelization during heat sterilization of glucose in a neutral pH range. However, since the pH is in the neutral range, the damage to blood vessels is naturally suppressed.

[0003]

Therefore, the inventors have completed the present invention by finding that vascular damage caused by the pH being in an acidic range or being hypertonic can be reduced by adding a predetermined amount of citric acid.

[0004]

The present inventors have discovered that an appropriate amount of citrate (including citrate ion added as a pH adjuster or a stabilizer) suppresses phlebitis.
In general, infusions for peripheral veins contain organic acid ions of 20 mEq / L to 50 as additives such as alkalizing agents and pH adjusters.
Although contained up to about mEq / L, the effect of reducing phlebitis was recognized by converting all or most of the organic acid ions into citrate ions. Also, 15 mEq / L
The effect of reducing phlebitis was also confirmed by adding the above citrate ions. That is, as citrate ions, 15 mEq / L or more, preferably 15 mEq / L to 5
The inventors have found that the ability to induce phlebitis of conventional infusion solutions for peripheral veins is reduced by adding or blending 0 mEq / L citrate ion, and completed the present invention.

That is, the present invention provides (1) a peripheral vein infusion solution containing 15 mEq / L or more of citrate ion as a phlebitis reducing agent, and (2) an osmotic pressure of 500 mOsm / L.
-1200 mOsm / L, the peripheral venous infusion according to (1), (3) the peripheral venous infusion according to (1), wherein the pH is 4.0 to 5.5, and (4) pH is 4.5. ~
Peripheral vein infusion according to (2) above, which is 7.0 (5)
Sugars 25 to 130 g / L, amino acids 0 to 40 g / L,
Na ⁺ 30 to 70 mEq / L, K ⁺ 10 to 30 mE
q / L, Mg ²⁺ 0-10 mEq / L, Ca ²⁺ 0
^{~10mEq / L, Cl - 30~70mEq /} L and above, wherein the containing citrate ion 15~50mEq / L (1) ~ ( 4) , wherein the peripheral venous transfusions (6) citrate ions Of 15 mEq / L or more for suppressing the onset of phlebitis, (7) Inhibiting the onset of phlebitis characterized by containing citrate or citric acid (6) The above-mentioned peripheral vein infusion solution.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION
As citrate, 15mEq as citrate ion
/ L or more, preferably 15 to 50 mEq / L
Good. As a source of citrate ions, citrate
(For example, trisodium citrate 2H _TwoO, three citric acid
Potassium / H_TwoO) and citric acid.
If desired, lactate, acetate, etc. may be added.
Good.

As the sugar contained in the infusion solution of the present invention, various sugars can be blended, but reducing sugar is preferably used. Examples of the reducing sugar include glucose, fructose, maltose, and the like, and these reducing sugars may be used as a mixture of two or more kinds. Further, a mixture obtained by adding sorbitol, xylitol, glycerin or the like to these reducing sugars may be used. The sugar is preferably about 20 to 140 g / L, preferably about 25 to 130, during transfusion.
g / L, more preferably about 30 to 100 g / L may be added.

The infusion solution of the present invention may contain an amino acid and an electrolyte. Examples of the amino acids include various amino acids (essential amino acids, non-essential amino acids) conventionally contained in amino acid infusions for the purpose of nutritional supplementation to the living body. For example, L-isoleucine, L-leucine, L-valine, L-lysine, L-methionine, L-
Phenylalanine, L-threonine, L-tryptophan, L-arginine, L-histidine, glycine, L-
Alanine, L-proline, L-aspartic acid, L-serine, L-tyrosine, L-glutamic acid, L-cysteine and the like are exemplified. These amino acids do not necessarily have to be used in the form of free amino acids, and include inorganic acid salts (for example, L-lysine hydrochloride, etc.) and organic acid salts (for example, L-lysine hydrochloride).
L-lysine acetate, L-lysine malate, etc., in-vivo hydrolysable ester (eg, L-tyrosine methyl ester, L-methionine methyl ester, L-methionine ethyl ester, etc.), N-substituted Body (eg N
-Acetyl-L-tryptophan, N-acetyl-L-
Cysteine, N-acetyl-L-proline, etc.), dipeptides in which the same or different amino acids are peptide-bonded (for example, L-tyrosyl-L-tyrosine, L-alanyl-L-tyrosine, L-arginyl-L-tyrosine). , L-
Tyrosyl-L-arginine) and the like. The amino acid may be added to the infusion solution at about 0 to 40 g / L, preferably about 0 to 30 g / L.

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

The following compounds may be mentioned as preferred embodiments of the electrolyte component for supplying the electrolyte ions. Sodium: sodium citrate, sodium chloride, sodium lactate, sodium acetate, sodium sulfate, sodium glycerophosphate, potassium: potassium citrate, potassium dihydrogen phosphate,
Potassium chloride, potassium glycerophosphate, potassium sulfate, potassium acetate, potassium lactate, calcium: calcium gluconate, calcium chloride,
Calcium glycerophosphate, calcium lactate, calcium pantothenate, calcium acetate, magnesium: magnesium sulfate, magnesium chloride,
Examples thereof include magnesium glycerophosphate, magnesium acetate and magnesium lactate. Further, phosphorus: potassium dihydrogen phosphate, potassium glycerophosphate, sodium glycerophosphate, magnesium glycerophosphate, calcium glycerophosphate, zinc: zinc sulfate, zinc chloride, zinc gluconate, zinc lactate, zinc acetate, etc. may be included.

The types, blending ratios and concentrations of sugar, amino acid and electrolyte in the infusion preparation of the present invention can be appropriately adjusted according to the intended use, the disease and symptoms of the patient to be administered, but preferably at least (1) And more preferably an infusion solution containing at least the following composition (2).

(1) Sodium 30-70 mEq /
L, potassium 10 to 30 mEq / L, calcium 0
~ 10 mEq / L, magnesium 0 ~ 10 mEq
/ L, chlorine 30 to 70 mEq / L, citric acid 15 to 5
0 mEq / L or (2) sugar 25-130 g /
L, amino acid 0-40 g / L, Na ⁺ 30-70 m
Eq / L, K ⁺ 10 to 30 mEq / L, Mg ²⁺ 0
-10 mEq / L, Ca ²⁺ 0-10 mEq / L, C
l ^- 30~70mEq / L and citrate ions 15
~ 50 mEq / L.

The infusion solution of the present invention can be prepared by various methods. For example, each of the above components is dissolved in suitable purified water (for example, water for injection), and the pH is adjusted by a conventional method (for example, citric acid). Using as a pH adjuster) about 4.5-7.
It is adjusted to about 0, preferably about 5.0 to 7.0. The infusion solution of the present invention may contain an anti-coloring agent (for example, thioglycerol, dithiothreitol, etc.) in order to prevent coloration during sterilization and storage, and the amount of these anti-coloring agents added is Usually, it is about 1% (W / V) or less. Furthermore, vitamins (eg, vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin K, etc.) and analogs of these vitamins may be added to the infusion solution of the present invention.

The infusion solution of the present invention can be sterilized by heating,
The heat sterilization is performed by, for example, filling the infusion solution into a glass container or a plastic container (for example, polypropylene, polyethylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, etc.) (for example, bag, bottle, etc.), and then inert gas. (For example, nitrogen gas, helium gas, etc.) is substituted, and after sealing, it is subjected to a sterilization process. The sterilization step can be performed according to a conventional method, for example, high pressure steam sterilization, hot water immersion sterilization, hot water shower sterilization and the like. When using a plastic container, it is preferable to sterilize in an atmosphere containing substantially no oxygen.

The heat-sterilized infusion preparation may be used as it is or diluted with water, or may be used alone or in combination with other infusion preparations (eg, fat emulsion, sugar infusion, etc.), drugs, etc. Administered intravenously.

[0016]

Example 1 Example 1 (30 mEq / as citrate ion)
L): 7.35 g of sodium citrate dihydrate was dissolved in water for injection to make 100 mL, and 20 mL thereof was added to 500 mL of a commercially available low-concentration amino acid infusion solution (Aminofreed) for preparation. Example 2 (15 mEq / L as citrate ion): 7.35 g of sodium citrate dihydrate was dissolved in water for injection to make 100 mL, and 10 mL thereof was added to 1 bag of commercially available low-concentration amino acid infusion solution (Aminofreed) 500 mL. Prepared. Comparative Example 1 (7.5 mEq / L as citrate ion): 7.35 g of sodium citrate dihydrate was dissolved in water for injection to make 100 mL, and 5 mL of the solution was added to 500 mL of a commercially available low-concentration amino acid infusion solution (Aminofreed). Was prepared. Comparative Example 2: Commercially available low-concentration amino acid infusion (Aminofreed)
Was used as is.

Commercially available low-concentration amino acid infusion (Aminofreed) has a pH of 6.7 and an osmotic pressure ratio to physiological saline of 3
Is hypertonic. The above-prepared examples and comparative examples also have pH values.
6.7, the osmotic pressure ratio was almost the same as 3. Therefore, phlebitis due to hypertonicity was expected.

[Test 1] Histopathological examination Japanese white male rabbit (about 15 weeks old, weight 2.5 to 3.5 kg) 1
120 mL / kg of each of the infusion solutions obtained in Examples 1 and 2 and Comparative Examples 1 and 2 was administered to the ear veins of 6 animals in a group at a rate of 10 mL / kg / hr for 12 hours. Twenty-four hours after the end of administration, the rabbit was sacrificed by anesthesia, and 3-1 from the tip of the indwelling needle of the ear to the heart
Tissues containing administration veins of 0 mm (proximal part) and 20 to 30 mm (distal part) were collected and fixed with 10% neutral buffered formalin solution.
An HE-stained sample was prepared from this, and histopathological examination was performed according to the evaluation criteria shown in Table 1 below. The evaluation results are shown in Table 2.

[0019]

[Table 1]

[0020]

[Table 2]

The infusion prepared in Examples 1 and 2 (infusion containing 30 mEq / L or 15 mEq / L of sodium citrate) did not cause any damage, whereas Comparative Example 1
With the infusion solution prepared in the above (infusion solution containing 7.5 mEq / L of sodium citrate), 4 of 6 cases were impaired. Further, in Comparative Example 2 in which sodium citrate was not added, vasculopathy was observed in all 6 cases. Therefore, it was considered that addition of 7.5 mEq / L as citrate ion was not sufficient, and addition of 15 mEq / L or more was better.

Example 3 The following electrolytes and glucose were added to water for injection and dissolved, and the pH was adjusted to 4.9 with citric acid to make 1000 mL, and an aqueous solution having the following composition was obtained. Glucose 35g Sodium chloride 0.88g Potassium chloride 1.49g Sodium citrate dihydrate 1.96g Magnesium sulfate heptahydrate 0.62g

Composition Glucose 3.5% Na + 35mEq / L K + 20mEq / L Mg ++ 5mEq / L Cl- 35mEq / L SO ₄ 2-5mEq / L Citrate3- 25mEq / L

Comparative Example 3 The following electrolytes and glucose were added to water for injection and dissolved, and the pH was adjusted to 4.9 with lactic acid to 1000 mL to obtain an aqueous solution having the following composition. Glucose 35g Sodium chloride 0.88g Potassium chloride 1.49g Sodium lactate (50% liquid) 4.48g Magnesium sulfate heptahydrate 0.62g

Composition Glucose 3.5% Na + 35mEq / L K + 20mEq / L Mg ++ 5mEq / L Cl- 35mEq / L SO ₄ 2-5mEq / L Lactate-23mEq / L

Comparative Example 4 The following electrolytes and glucose were added to water for injection and dissolved, and the pH was adjusted to 4.9 with acetic acid to 1000 mL to obtain an aqueous solution having the following composition. Glucose 35g Sodium chloride 0.88g Potassium chloride 1.49g Sodium acetate-3-hydrate 2.72g Magnesium sulfate-7-hydrate 0.62g

Composition Glucose 3.5% Na + 35mEq / L K + 20mEq / L Mg ++ 5mEq / L Cl- 35mEq / L SO ₄ 2-5mEq / L Acetate-23mEq / L All the obtained infusion solutions had pH 4.9 and physiological saline. It was almost isotonic with the liquid. Therefore, phlebitis due to low pH was expected.

[Test 2] Histopathological examination Japanese white male rabbits (about 15 weeks old, body weight 2.5 to 3.5 kg) were placed in 6 groups of 6 auricular veins in Example 3, Comparative Example 3 and Comparative Example 4. 80 mL / kg of each obtained infusion solution was administered at a rate of 10 mL / kg / hr for 8 hours. Twenty-four hours after the end of administration, the rabbits were sacrificed by hyperanesthesia, and tissues including administration veins of 3 to 10 mm (proximal part) and 20 to 30 mm (distal part) on the heart side from the tip of the indwelling needle of the auricle were collected. And fixed with 10% neutral buffered formalin solution. From now on
E-stained specimens were prepared and histopathological examination was performed according to the evaluation criteria shown in Table 1 above. The results are shown in Table 3.

[0029]

[Table 3]

In the infusion solution of the present invention prepared in Example 3 (infusion solution using citrate as an alkalizing agent), no damage was observed, whereas Comparative Example 3 using lactate and acetate were used. In Comparative Example 4, the mild vascular disorder was 6
It was observed in 4 or 5 cases.

[Example 4] The following chemicals were filled and closed in each chamber of a plastic bag made of polyethylene and having two separable partition walls to obtain a chemical shown in the composition. [Medicinal solution prescription] (First chamber) The following components were dissolved in water for injection and the pH was adjusted to 6.9 with citric acid to make 300 ml. L-leucine 4.20 g L-isoleucine 2.40 g L-valine 2.40 g Lysine hydrochloride 3.93 g L-threonine 1.71 g L-tryptophan 0.60 g L-methionine 1.17 g L-cysteine 0.30 g L-phenylalanine 2.10 g L-tyrosine 0.15 g L -Arginine 3.15g L-histidine 1.50g L-alanine 2.40g L-proline 1.50g L-serine 0.90g aminoacetic acid 1.77g L-aspartic acid 0.30g L-glutamic acid 0.30g dipotassium phosphate 1.74g sodium bisulfite 0.06g Citric acid

(Second chamber) The following components were dissolved in water for injection and the pH was adjusted to 5.0 with citric acid to make 700 ml. Glucose 75.0 g Sodium chloride 0.80 g Sodium citrate (.dihydrate) 1.96 g Calcium gluconate 1.12 g Magnesium sulfate (.7 hydrate) 0.62 g Zinc sulfate 1.4 mg Sodium bisulfite 0.03 g Citric acid Suitable amount

When the partition walls of these two chambers were opened, the pH of the chemical solution was 6.7, the osmotic pressure ratio was about 3, and the composition was as follows. Amino 3.0% glucose 7.5% Na + 35mEq / L K + 20mEq / L Ca ++ 5mEq / L Mg ++ 5mEq / L CL- 35mEq / L SO 4 2 - 5mEq / L phosphate 10mmol / L Citrate3- 43mEq / L Gluconate- 5mEq / L zinc 5μmol / L

Example 5 The following electrolytes and glucose were added to water for injection and dissolved, and the pH was adjusted to 5.3 with citric acid to make 1000 mL, and an aqueous solution having the following composition was obtained. Glucose 30.0g Sodium chloride 0.88g Potassium chloride 1.12g Potassium dihydrogen phosphate 0.68g Sodium citrate (.dihydrate) 1.96g Calcium chloride (.dihydrate) 0.37g Magnesium sulfate (.7hydrate) 0.62g Acid proper amount

The chemical solution had a pH of 5.3 and an osmotic pressure ratio of about 1, and the composition was as follows. Glucose 3.0% Na + 35mEq / L K + 20mEq / L Ca ++ 5mEq / L Mg ++ 5mEq / L CL- 35mEq / L SO ₄ 2-5mEq / L Phosphorus 5mmol / L Citrate3- 28mEq / L

[Test 3] The infusion solutions prepared in Examples 4 and 5 were administered to the ear vein of rabbits under the same administration conditions as in Test 1, and the degree of phlebitis was evaluated using the same method. did. As a result, none of the infusion solutions prepared in Example 4 and Example 5 had the vasculopathy as described below.

[0037]

[Table 4]

[0038]

INDUSTRIAL APPLICABILITY The present invention reduces the occurrence of local reactions such as vascular pain and phlebitis due to peripheral venous infusion, and improves the safety of peripheral venous infusion.

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Claims (7)

[Claims] 1. A citrate ion as an agent for reducing phlebitis
A peripheral vein infusion characterized by containing 5 mEq / L or more. 2. An osmotic pressure of 500 mOsm / L to 1200.
The infusion solution for peripheral vein according to claim 1, which is mOsm / L. 3. The peripheral vein infusion solution according to claim 1, which has a pH of 4.0 to 5.5. 4. The infusion solution for peripheral vein according to claim 2, which has a pH of 4.5 to 7.0. 5. Sugar 25 to 130 g / L, amino acid 0
-40 g / L, Na ⁺ 30-70 mEq / L, K ⁺¹
0-30 mEq / L, Mg ²⁺ 0-10 mEq / L,
Ca ²⁺ 0-10 mEq / L, Cl ^- 30-70 m
Eq / L and a citrate ion 15-50mEq / L are contained, The infusion solution for peripheral veins of Claims 1-4 characterized by the above-mentioned. 6. A peripheral vein infusion solution for suppressing the onset of phlebitis, which contains 15 mEq / L or more of citrate ions. 7. The infusion solution for peripheral vein according to claim 6, which suppresses the development of phlebitis, which contains citrate or citric acid.