JPH0517431A - Stabilized cysteine solution - Google Patents

Abstract

(57) [Summary] (Corrected) [Composition] Cysteine contains 20-60% polyvalent alcohol.
Solution and 0.01 to 2.0% magnesium ascorbyl phosphate magnesium salt are uniformly dissolved in an aqueous solution.
[Effect] It is a liquid that dramatically improves the liquid stabilization of cysteine, has a pH of 3.0 to 6.5, and can also be used as an auxiliary additive for infusion or an intravenous injection.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to liquid storage stabilization of cysteine. More specifically, the present invention can be used as an additive for injections and infusions, and is characterized by improving its usability and facilitating operability and preventing bacterial contamination.

[0002]

2. Description of the Related Art Stabilization of cysteine in a liquid has been tried so far, but it is known that it is difficult to stabilize cysteine in a liquid and prevent decomposition by high-pressure steam sterilization. Clinically, cysteine is one of the essential amino acids in the body, is used as an antidote for the drug allergic, and is used as a raw material for biosynthesis of enzymes and proteins in vivo. It is also very important for nutritional supplementation as one of the essential amino acids in a high calorie infusion solution (basic solution for central parenteral nutrition), and is effective for treatment of liver damage and maintenance of biological functions. But,
Cysteine has poor storage stability and is easily oxidized by light and oxygen to produce cystine, which is hardly soluble in water. Especially when it is in liquid form.

Conventionally, cysteine has been used as a powder and dissolved before use, but it cannot be said that the powder has good storage stability. In fact, a relatively stable hydrochloride is used. Has a pH of 1 or less when dissolved in water, which is not preferable in terms of safety to living organisms. However, despite the above-mentioned problems, administration of cysteine is very effective and effective in drug allergy and nutritional supplementation.

[0004]

However, since the conventional method of dissolving a powdered preparation at the time of use and aseptically adding it to an infusion agent or the like is troublesome in operation and causes secondary contamination by bacteria, etc. Problems have been pointed out. Further, when using a hydrochloride, there is a problem that the usable amount is limited due to its strong acidity. When cysteine is dissolved in a solution such as water, a cystine precipitate begins to be deposited after about a dozen hours, and most of cysteine is decomposed. This is especially noticeable when oxygen and light are present. Cysteine is also thermally decomposed by high-pressure steam sterilization to produce cystine and hydrogen sulfide. Nitrogen encapsulation and antioxidants such as sodium bisulfite and ascorbic acid are sometimes used to prevent the decomposition of cysteine in the liquid, but the effect is only a few days, far from liquid stabilization. Sodium bisulfite is reductively decomposed to generate hydrogen sulfide, and ascorbic acid has a weak thermal stability, and thus causes autolysis and causes browning. Further, its liquid property is more unstable near neutrality, and therefore it must be strongly acidic at pH 1-2, which is not preferable in terms of biological safety.

The present invention has been achieved through intensive research aimed at solving these problems.

[0006]

The present invention is a polyvalent alcohol.
It has been found that liquid stabilization of cysteine is achieved by magnesium and magnesium ascorbyl phosphate. The polyhydric alcohol suppresses the reaction of cysteine in a liquid, and the magnesium salt of ascorbic acid phosphate acts as an antioxidant that suppresses the oxidative degradation of cysteine and enhances the stability.

The polyhydric alcohol used in the present invention is preferably highly safe for living organisms and has good water solubility. For example, ethylene glycol, propylene glycol
, Glycerin, xylitol, sorbitol, mannitol, threose, glycerin, glycerophosphate,
It is selected from ascorbic acid, hexanediol, dextrin, polyethylene glycol and the like. Among these, polyvalent alcohols having 2 to 6 carbon atoms are preferable. The amount of the polyhydric alcohol used is preferably 20% or more, preferably 3%.
0 to 50% is the best in stability. If it is 20% or less, the stability is not sufficient and the effect is scarce. Further, when it is 60% or more, it is inconvenient in terms of solubility and stability. The amount of the magnesium ascorbyl phosphate magnesium salt used in the present invention is preferably 0.01 to 2.0%. If it is 0.01% or less, the stabilizing effect is not sufficient, and if it is 2.0% or more, the solubility is inconvenient. As an antioxidant, it is necessary to maintain efficacy for a long time, have good thermal stability, and be able to exert sufficient efficacy under neutral liquid conditions. In that respect, ascorbic acid phosphate magnesium salt is preferable. is there. The pH of the stabilized cysteine solution of the present invention is 3.0 to 6.5 for stability and safety. When the pH is less than 3.0, it is not preferable in terms of safety to the living body, and when the pH is 6.5 or more, the stability is poor.

The stabilized cysteine solution of the present invention may contain conventionally known components in addition to these components. That is, it may contain a buffering agent, a preservative, a chelating agent, a pH adjusting agent, an inorganic salt and the like.

Since the stabilized cysteine solution of the present invention is a solution-form cysteine obtained as described above, a necessary and sufficient amount should be aseptically added to the infusion solution by using both sword needles and the like at the time of use. Use or inject directly into a syringe for intravenous injection.

[0010]

The stabilized cysteine solution according to the present invention contains polyvalent alcohol and magnesium ascorbyl phosphate magnesium salt, so that cysteine can be kept stable in a liquid state for a long period of time.

[0011]

【Example】

(Example 1) 2.5 g of cysteine and 0.1 g of ascorbic acid phosphate magnesium salt were dissolved in 20 g of purified water, and 30.0 g of glycerin was added and mixed. 0.1N
PH 5.1 with hydrochloric acid or 0.1N sodium hydroxide solution
The total amount was adjusted to 100 g with purified water. 15 g of this solution was dispensed into a 20 ml glass vial, the head space gas was replaced with nitrogen, and the solution was sealed with butyl rubber. Four
The cysteine content after 4 weeks at 0 ° C was 96.7%, and no precipitation was observed, indicating good stability.

Example 2 1.0 g of cysteine and 0.1 g of ascorbic acid phosphate magnesium salt were dissolved in 20 g of purified water, and 50.0 g of glycerin was added and mixed. The pH was adjusted to 6.0 with 0.1N hydrochloric acid or 0.1N sodium hydroxide solution, and the total amount was adjusted to 100 g with purified water. 15 g of this solution was dispensed into a 20 ml glass vial, the head space gas was replaced with nitrogen, and the solution was sealed with butyl rubber. The cysteine content after 4 weeks at 40 ° C is 9
The content was 7.7% and no precipitation was observed, indicating good stability.

Example 3 2.5 g of cysteine and 1.0 g of ascorbic acid phosphate magnesium salt were dissolved in 20 g of purified water, and 25.0 g of glycerin was added and mixed. The pH was adjusted to 4.8 with 0.1N hydrochloric acid or 0.1N sodium hydroxide solution, and the total amount was adjusted to 100 g with purified water. 15 g of this solution was dispensed into a 20 ml glass vial, the head space gas was replaced with nitrogen, and the solution was sealed with butyl rubber. The cysteine content after 4 weeks at 40 ° C is 9
It was 4.5% and no precipitation was observed.

(Example 4) 2.5 g of cysteine and 0.1 g of ascorbic acid phosphoric acid ester magnesium salt were dissolved in 20 g of purified water, and 50.0 g of propylene glycol was added and mixed. The pH was adjusted to 5.1 with 0.1N hydrochloric acid or 0.1N sodium hydroxide solution, and the total amount was adjusted to 10 with purified water.
It was set to 0 g. Add 1 part of this solution to a 20 ml glass vial.
After dispensing 5 g, the head space gas was replaced with nitrogen and the container was sealed with butyl rubber. The cysteine content after 4 weeks at 40 ° C. was 83.7%, but a slight white precipitate was observed.

(Example 5) 1.5 g of cysteine and 0.5 g of ascorbic acid phosphate magnesium salt were dissolved in 20 g of purified water, and 35.0 g of glycerin was added and mixed. The pH was adjusted to 3.5 with 0.1N hydrochloric acid or 0.1N sodium hydroxide solution, and the total amount was adjusted to 100 g with purified water. 15 g of this solution was dispensed into a 20 ml glass vial, the head space gas was replaced with nitrogen, and the solution was sealed with butyl rubber. The cysteine content after 4 weeks at 40 ° C is 9
It was 6.1% and no precipitation was observed.

(Example 6) 1.5 g of cysteine and 2.0 g of magnesium ascorbyl phosphate ester were dissolved in 20 g of purified water, and 10.0 g of sorbitol and 40.0 g of glycerin were added and mixed. 0.1N hydrochloric acid or 0.
The pH was adjusted to 3.2 with 1N sodium hydroxide solution, and the total amount was adjusted to 100 g with purified water. 15 g of this solution was dispensed into a 20 ml glass vial, the head space gas was replaced with nitrogen, and the solution was sealed with butyl rubber. The cysteine content after 4 weeks at 40 ° C. was 93.4%, and no precipitation was observed, indicating sufficient stability.

(Example 7) The solution of (Example 5) was added to 110
Sterilized by autoclaving at 5 ° C for 5 minutes. The cysteine content after 4 weeks at 40 ° C. was 93.3%, and no precipitation was observed.

(Example 8) The solution of (Example 6) was added to 110
Sterilized by autoclaving at 5 ° C for 5 minutes. The cysteine content after 4 weeks at 40 ° C. was 94.8%, and no precipitation was observed.

Comparative Example 1 2.5 g of cysteine and 0.02 g of magnesium ascorbyl phosphate magnesium salt were dissolved in 20 g of purified water, and 70.0 g of glycerin was added and mixed. The pH was adjusted to 6.2 with 0.1N hydrochloric acid or 0.1N sodium hydroxide solution, and the total amount was adjusted to 100 g with purified water. 15 g of this solution was dispensed into a 20 ml glass vial, the head space gas was replaced with nitrogen, and the solution was sealed with butyl rubber. Cysteine content after 4 weeks at 40 ° C is 8
Although it was 1.5%, precipitation was observed.

Comparative Example 2 2.5 g of cysteine was dissolved in 20 g of purified water, and 30.0 g of glycerin was added and mixed. The pH was adjusted to 3.7 with 0.1N hydrochloric acid or 0.1N sodium hydroxide solution, and the total amount was adjusted to 100 g with purified water. 15 g of this solution was dispensed into a 20 ml glass vial, the head space gas was replaced with nitrogen, and the solution was sealed with butyl rubber. Cysteine content after 4 weeks at 40 ° C is 6
Although it was 4.1%, a large amount of white precipitate was observed and sufficient stability was not shown.

(Comparative Example 3) The solution of (Comparative Example 2) was added to 110
Sterilized by autoclaving at 5 ° C for 5 minutes. The cysteine content after 4 weeks at 40 ° C. was 12.0%, and a large amount of precipitate was observed.

Comparative Example 4 1.0 g of cysteine was dissolved in 90 g of purified water, pH was adjusted to 3.5 with 0.1N hydrochloric acid or 0.1N sodium hydroxide solution, and the total amount was adjusted to 1 with purified water.
It was set to 00 g.

1 part of this solution in a 20 ml glass vial
After dispensing 5 g, the head space gas was replaced with nitrogen and the container was sealed with butyl rubber. After 4 weeks at 40 ° C, the cysteine content was 5% or less, and a large amount of white precipitate was observed.

(Comparative Example 5) 2.5 g of cysteine and 0.005 g of magnesium ascorbyl phosphate were dissolved in 90 g of purified water, adjusted to pH 4.5 with 0.1N sodium hydroxide solution, and purified water was added. Was 100 g.

1 part of this solution in a 20 ml glass vial
After dispensing 5 g, the head space gas was replaced with nitrogen and the container was sealed with butyl rubber. The cysteine content after 4 weeks at 40 ° C. was 32.6%, and a large amount of white precipitate was observed.

(Comparative Example 6) 1.5 g of cysteine and 0.3 g of ascorbic acid phosphate magnesium salt were dissolved in 90 g of purified water, and p was added with 0.1N sodium hydroxide solution.
The amount was adjusted to H3.5, and the total amount was adjusted to 100 g with purified water.

1 part of this solution in a 20 ml glass vial
After dispensing 5 g, the head space gas was replaced with nitrogen and the container was sealed with butyl rubber. The cysteine content after 4 weeks at 40 ° C. was 51.9%, and a large amount of white precipitate was observed.

The cysteine quantification method of the present example and the comparative example was performed at a color of 750 nm with a Folin-Ciocalteu reagent.
The absorbance was measured and determined from the calibration curve.

[0029]

INDUSTRIAL APPLICABILITY The present invention makes it possible to prepare a stable cysteine solution by dramatically increasing the storage stability of cysteine in a liquid state with a solvent that is safe for living bodies, and to add this solution to an infusion solution or the like. The use as an agent also has the effect that a necessary and sufficient amount of cysteine can be safely administered.

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Claims (5)

[Claims] 1. A stabilized liquid obtained by uniformly dissolving cysteine in an aqueous solution containing 20 to 60% polyvalent alcohol and 0.01 to 2.0% magnesium ascorbyl phosphate magnesium salt. A stabilized cysteine solution, characterized in that 2. The stabilized cysteine solution according to claim 1, wherein the polyvalent alcohol used in the stabilized cysteine solution has 2 to 6 carbon atoms. 3. The stabilized cysteine solution according to claim 1, wherein the polyvalent alcohol used in the stabilized cysteine solution is glycerin. 4. The stabilized cysteine solution according to claim 1, which is used by adding the stabilized cysteine solution to an infusion solution. 5. The stabilized cysteine solution has a pH of 3.
It is 0-6.5, The stabilized cysteine solution of Claim 1 characterized by the above-mentioned.