JPH026335B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing an infusion solution that contains glucose, amino acids, and electrolytes in one drug and is highly safe. Glucose, amino acids, and electrolytes, which are the main components of infusions administered as complete parenteral nutrition, include isoleucine, leucine,
In addition to essential amino acids such as methionine, phenylalanine, threonine, valine, tryptophan, lysine, arginine, and histidine, aspartic acid, glutamic acid, alanine, cystine, aminoacetic acid, proline, serine, tyrosine, etc. are appropriately blended as the electrolyte. Salts that supply potassium, sodium, magnesium, calcium, phosphorus, and chloride ions are used, but they are generally used in the form of chlorides, sulfates, phosphates, and organic acid salts. Infusion formulations that contain these key ingredients together, glucose, amino acids, and electrolytes, have not yet been manufactured due to stability problems associated with acid combination, such as a tendency for coloration; currently, separately produced glucose - Electrolyte preparations and amino acid preparations are mixed before use and administered to patients. Combining these two formulations into a single formulation reduces the time required for compounding at the time of use and reduces the possibility of bacterial contamination, but the biggest advantage of the combined formulation is that The problem is that the browning reaction (Maillard reaction) that occurs between sugar and amino acids in an aqueous solution causes the preparation to be easily colored, resulting in poor sterilization resistance and storage stability. As a result of various studies on preventing the above-mentioned coloring of aqueous solutions containing glucose, amino acids, and electrolytes, the present inventor found that coloring is PH-dependent, as described below, and that the higher the PH, the more likely it is to be colored. The present invention was completed after discovering that coloring varies greatly depending on the type of acid salt, and that among organic acid salts, lactate causes the least amount of coloring. That is, the present invention is an infusion solution used for complete parenteral nutrition containing glucose, amino acids and electrolytes,
In infusions using organic acid salts or mixtures of organic and inorganic acid salts as electrolytes, lactate is used as the organic acid salt, and PH is adjusted with lactic acid and/or mineral acids.
There is a method for manufacturing an infusion solution which consists of adjusting the amount of 4.5 to 5.5. The present invention will be explained in detail below. When aqueous solutions with the three compositions shown in Table 1 below are melt-sealed in an ampoule under nitrogen atmosphere and heated at 100°C for 30 or 60 minutes, the liquids with compositions A and B will be colored yellow to brown, and their strength will change. can be expressed as absorbance at 400 nm. Composition C, which contains amino acids and electrolytes but no glucose, shows almost no coloration after heating, but coloration occurs in compositions A and B, where glucose and amino acids coexist, and in particular, A, which contains electrolytes, is more markedly colored than B. .

[Table] Also, as is clear from Table 2 below, when the PH of composition A is changed with hydrochloric acid or sodium hydroxide, the PH
The higher the value, the greater the coloring after heating.

[Table] Also, as is clear from Table 3 below, it was found that electrolytes are involved as a factor promoting the coloring reaction, so among the components of composition A, the concentration of sodium acetate was changed and heated at 100℃. It was found that the intensity of coloring was dependent on the concentration of sodium acetate.

【table】

[Table] Hydrochloric acid appropriate amount
pH 4.6
*Contents are the same as in Table 1 Even if the concentration of other electrolytes was changed, the intensity of coloring due to heating did not change and the coloring remained the same. To summarize the above results, it can be said that the coloration of composition A is caused by glucose and amino acids, and is promoted by sodium acetate. Therefore, the results shown in Table 4 below are a comparison of the effects of various organic acid salts on the browning reaction between glucose and amino acids, and the results show that the degree of coloring changes significantly depending on the type of organic acid salt, Among the organic acid salts affected, lactate has the least influence, and citrate has the greatest influence.

[Table] Ampoule space nitrogen Figure 1 shows the following composition Glucose 18.7% (weight) Amino acid group ^* 4% Sodium chloride 0.0346% Monopotassium phosphate 0.082% Magnesium sulfate 0.103% Calcium chloride 0.058% Sodium acid sulfite 0, 00.2, 00.4% Hydrochloric acid Appropriate amount Ampoule space nitrogen This is a graph showing the relationship between pH and the effect of adding acidic sodium sulfite, and it can be seen from this that the addition of acidic sodium sulfite has the effect of further reducing coloring. For comparison, we have shown the results when sodium acetate was used instead of sodium lactate, and it can be seen that the effect of sodium lactate is more pronounced when the pH is high. Note that the PH of the infusion containing glucose, amino acids, and electrolytes is lower than the PH range shown in Figure 1, that is, PH4.5.
A lower concentration is better in terms of coloring, but the buffering properties of the solution are strong, which is not preferable for living organisms if a large amount is to be injected intravenously. In addition, the higher the PH, the easier it is to be colored, so the desired PH
The range is 4.5-5.5. As is clear from the above detailed description, the present invention provides an electrolyte in the form of an organic acid salt in an infusion containing an electrolyte that supplies glucose, amino acids, and potassium, sodium, magnesium, calcium, phosphate, and chloride ions. In addition, lactic acid and/or mineral acid are used to adjust the pH to 4.5 to 5.5, and water-soluble sulfite, acid sulfite, or pyrosulfite is added. It is something to do. Examples are given below, but they are not intended to limit the scope of the present invention in any way. Example 1 Glucose 100g Arginine hydrochloride 2.7g Isoleucine 2.5g Histidine hydrochloride 1.4g Leucine 3.0g Aminoacetic acid 4.1g Lysine hydrochloride 3.9g Sodium chloride 0.242g Methionine 2.6g Monopotassium phosphate 0.574g Phenylalanine 1.7g Magnesium sulfate 0.721g threonine 1.7g Calcicum chloride 0.408g Tryptophan 0.9g Sodium lactate 5.6g Valine 2.5g Sodium acid sulfite 0.4g Dissolve the above in 700ml of distilled water for injection, and adjust the pH to 5 by adding 10% lactic acid. Add distilled water to bring the total volume to 1, and pass through a Millipore filter to bring it to 500.
After filling into a ml infusion vial, it was sterilized according to the Japanese Pharmacopoeia General Tests Sterilization Method. A clear and colorless infusion solution was obtained. Example 2 In Example 1, the pH was adjusted to 5.5 by using N/10-hydrochloric acid instead of 10% lactic acid.
The procedure was then carried out in the same manner as in Example 1 to obtain an almost colorless and clear infusion solution. Example 3 In Example 1, 0.857 g of calcium lactate was used instead of calcium chloride, and the pH was adjusted to 5 by adding N/10-hydrochloric acid. The procedure was then carried out in the same manner as in Example 1 to obtain a colorless and clear infusion solution.

[Brief explanation of drawings]

FIG. 1 is a graph showing the relationship between sodium lactate and sodium acetate in infusions and pH, and the influence of addition of acidic sodium sulfite salt.

Claims (1)

[Claims] 1 Glucose, amino acids and electrolytes such as potassium, sodium, magnesium, calcium,
Total parenteral nutrition infusions containing salts that supply phosphorus and chloride ions, using lactate as the organic acid salt in infusions that use organic acid salts or a mixture of organic and inorganic acid salts as electrolytes. death,
A method for producing an infusion solution, which further comprises adding a salt that forms sulfite ions in an aqueous solution, and adjusting the pH to 4.5 to 5.5 with lactic acid and/or mineral acid.