JP2022041058A - Sulfite-containing liquid - Google Patents

Abstract

To provide a liquid having improved stability and containing gallic acid or a gallic acid-bound compound.SOLUTION: The inventive liquid contains gallic acid or a gallic acid-bound compound, and a sulfite, erythorbic acid or a salt thereof and N-acetyl-L-cysteine.SELECTED DRAWING: None

Description

The present invention relates to a stabilizing solution of gallic acid or a gallic acid-binding compound containing sulfites.

Gallic acid and gallic acid-binding compounds having a galloyl group in the molecule are a kind of polyphenols widely used in foods and pharmaceuticals. Polyphenols have beneficial physiological activities for living organisms such as antioxidant activity, but on the other hand, they are unstable molecules that are easily oxidized by changes in temperature due to radicals, pH and heating, so they can be used as a solution. It is known that storage causes decomposition of polyphenols, generation of precipitates, discoloration of solutions, and the like.

A method of adjusting the pH to 5 or less by adding an antioxidant or L-ascorbic acid to the oxidation of this polyphenol has been proposed (Patent Document 1). It is also being considered to stabilize polyphenols by combining a plurality of antioxidants. For example, the antioxidant effects of ascorbic acid and α-tocopherol are considered to be a typical combination showing a synergistic effect. (Non-Patent Documents 1 and 2). It is believed that this is not only due to the individual effects, but also because ascorbic acid reduces the reactants produced by the elimination of radicals by α-tocopherol and regenerates them into α-tocopherol.
In addition, by using an antioxidant such as potassium disulfurous acid, which is known to enhance the stability of ascorbic acid, together with ascorbic acid, it is possible to effectively decompose, precipitate and color the epigallocatechin gallate by oxidation. It has been reported that it can be suppressed (Patent Document 2).

However, depending on the combination of antioxidants, some have synergistic effects such as ascorbic acid and α-tocopherol, while the antioxidant effect may be diminished by the offsetting effect, so multiple antioxidants are combined. Therefore, it is not always possible to suppress the oxidation of polyphenols, and it cannot be said that the stability of polyphenols can be improved.

Japanese Unexamined Patent Publication No. 2006-191851 Japanese Unexamined Patent Publication No. 2006-188436

Packer JE, Slater TF, Willson RL. Direct observation of a free radical interaction between vitamin E and vitamin C. Nature. 1979 Apr 19; 278 (5706): 737-8. Niki E, Noguchi N, Tsuchihashi H, Gotoh N. Interaction among vitamin C, vitamin E, and beta-carotene. Am J Clin Nutr. 1995 Dec; 62 (6 Suppl): 1322S-1326S.

The present invention relates to providing a liquid preparation containing gallic acid or a gallic acid-binding compound having improved stability.

As a result of diligent research, the inventors of the present application have added gallic acid or gallic acid to a liquid preparation containing a gallic acid-binding compound with sulfites, N-acetyl-L-cysteine and erythorbic acid or a salt thereof. It has been found that the stability of the acid-binding compound in a liquid preparation is improved.

That is, the present invention relates to the following 1) to 8).
1) A liquid preparation containing gallic acid or a gallic acid-binding compound, and sulfites, N-acetyl-L-cysteine and erythorbic acid or a salt thereof.
2) The liquid preparation of 1) containing sulfites at a concentration equal to or higher than that of gallic acid or a gallic acid-binding compound.
3) The liquid preparation of 1) or 2) containing N-acetyl-L-cysteine and erythorbic acid or a salt thereof in an equimolar concentration or more and a 5-fold molar concentration or less, respectively, with gallic acid or a gallic acid-binding compound.
4) Gallic acid or gallic acid-binding compound is gallic acid or a salt thereof, di-gallic acid or a salt thereof, lower alkyl esters of gallic acid, epigallocatechin gallate, epicatechingalate, pentagalloylglucose, glucogalin, tannic acid, Galloylbergenin, galloylalbutin and N2, N6-bis [N2, N6-bis (3,4,5-trihydroxybenzoyl) -licyl] -N- (2-aminoethyl) -lysineamide epigallocatechin gallate A liquid agent according to any one of 1) to 3), which is one or more selected from.
5) A method for stabilizing a gallic acid or a gallic acid-binding compound in a liquid preparation, which comprises a step of adding sulfites, N-acetyl-L-cysteine and erythorbic acid or a salt thereof.
6) The method of 5) in which sulfites are added so as to contain gallic acid or a gallic acid-binding compound at an equimolar concentration or higher.
7) The method of 5) or 6) in which N-acetyl-L-cysteine and erythorbic acid or a salt thereof are added so as to contain gallic acid or a gallic acid-binding compound in an equimolar concentration or more and a 5-fold molar concentration or less, respectively.
8) A stabilizer for a liquid preparation containing gallic acid or a gallic acid-binding compound containing sulfites, N-acetyl-L-cysteine and erythorbic acid or a salt thereof as active ingredients.

According to the present invention, since the stability of foods and pharmaceuticals containing gallic acid or gallic acid-binding compound is improved, manufacturing process control and quality control are facilitated, which can greatly contribute to the food industry and the pharmaceutical industry.

Evaluation of coloration of gallic acid at 4 ° C storage. Evaluation of coloration of gallic acid at 25 ° C. Changes in the quantitative values of galloyl groups when gallic acid is stored at 4 ° C. Changes in the quantitative values of galloyl groups when gallic acid is stored at 25 ° C. Evaluation of coloring of epigallocatechin gallate at 4 ° C. Evaluation of coloring of epigallocatechin gallate at 25 ° C. Changes in the absorbance of epigallocatechin gallate at 4 ° C. Changes in the absorbance of epigallocatechin gallate at 25 ° C. Evaluation of coloration of ethyl gallate at 4 ° C storage. Evaluation of coloration of ethyl gallate at 25 ° C. Changes in the absorbance of ethyl gallate at 4 ° C. Changes in the absorbance of ethyl gallate at 25 ° C.

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

In the present invention, the "liquid agent" means an aqueous liquid agent containing water, and may be any of an aqueous solution agent, a suspension agent, an emulsion and the like, but an aqueous solution agent is preferable.
The liquid preparation of the present invention is a liquid preparation containing gallic acid or a gallic acid-binding compound, and sulfites, N-acetyl-L-cysteine and erythorbic acid or a salt thereof, and the stability of the gallic acid or the gallic acid-binding compound is improved. It is a liquid agent.
In the present invention, "stability" means the stability of the gallic acid or the gallic acid-binding compound against oxidation, and "improved stability" means that the oxidation of the gallic acid or the gallic acid-binding compound is suppressed and precipitation occurs. And coloring is suppressed.

As shown in Examples described later, sulfites, N-acetyl-L-cysteine and erythorbic acid or salts thereof are useful for stabilizing gallic acid or gallic acid-binding compounds in liquid preparations. Therefore, sulfites, N-acetyl-L-cysteine and erythorbic acid or salts thereof can serve as stabilizers for stabilizing gallic acid or gallic acid-binding compounds in the liquid preparation, and these are blended in the liquid preparation. This makes it possible to stabilize gallic acid or a gallic acid-binding compound.

In the present invention, the "gallic acid-bonded compound" is a compound to which gallic acid is chemically bonded, and specifically, a compound in which gallic acid is ester-bonded or amide-bonded, that is, a compound having a galloyl group in the molecule. means. Examples of the gallic acid-binding compound include digallic acid, lower alkyl (1 to 6 carbon atoms) ester of gallic acid (for example, ethyl gallic acid, propyl gallic acid, butyl gallic acid, etc.), epigallocate gingalate, and epicateringalate. , Pentagalloylglucose, glucogalin, tannic acid, galloylbergenin, galloylalbutin, N2, N6-bis [N2, N6-bis (3,4,5-trihydroxybenzoyl) -lysyl] -N- (2) -Aminoethyl) -lysineamide (International Publication No. 2007/052641) and the like, but are not limited thereto.
The gallic acid or gallic acid-binding compound of the present invention may exist in a salt state in a liquid preparation, and the salt is not particularly limited, and examples thereof include alkali metal salts such as sodium and potassium.

Further, in the liquid preparation of the present invention, the inclusion of "gallic acid or gallic acid-binding compound" means that gallic acid or gallic acid-binding compound may be present in the liquid preparation, and other than the case where the compound is blended in the liquid. , Plants containing the compound or its extracts (eg, seaweeds, vegetables, fruits and grains such as citrus fruits and apples or their extracts, etc.), foods and drinks (eg, tea, wine, cacao, etc.) in liquid form. As a result of blending, the case where the compound is present in the liquid preparation is also included.

The concentration of the gallic acid or the gallic acid-binding compound in the liquid preparation of the present invention is not particularly limited, but is preferably 0.1 mM or more, more preferably 0.5 mM or more, more preferably 1 mM or more, and preferably. It is 75 mM or less, more preferably 50 mM or less, and more preferably 25 mM or less.

In the liquid preparation of the present invention, by using sulfites, N-acetyl-L-cysteine and erythorbic acid or a salt thereof in combination, the stability of gallic acid or gallic acid-binding compound in the liquid preparation is improved, and coloring and precipitation are performed. Can be suppressed. Sulfates, N-acetyl-L-cysteine and erythorbic acid or salts thereof are water-soluble and exhibit antioxidant effects in the neutral region, and thus can be blended in many pharmaceuticals and foods.

In the present invention, sulfites refer to salts that become sulfite ions, hydrogen sulfite ions, and disulfite (also known as pyrosulfite, metasulfurous acid) ions in an aqueous solution, and specifically, sulfites, sulfites, and sulfites. Examples thereof include hydrogen salts and hyposulfites. More specifically, for example, sodium sulfite, sodium sulfite, sodium hydrogen sulfite, sodium hyposulfite, potassium sulfite, potassium disulfite, potassium hydrogen sulfite, ammonium sulfite, ammonium disulfite, ammonium hydrogen sulfite and the like are preferable. Is potassium disulfite and sodium sulfite.
In the present invention, the sulfites may be one selected from various sulfites, or may be used in combination of two or more.

The concentration of sulfites in the liquid preparation of the present invention can be appropriately set according to the content of gallic acid or gallic acid-binding compound, but is equal to or more than the molar concentration of gallic acid or gallic acid-binding compound, preferably 1.5 times the molar concentration. Above, more preferably, it is twice the molar concentration or more. The upper limit is not particularly limited, and examples thereof include a 4.5-fold molar concentration or less, a 4-fold molar concentration or less, and a 3-fold molar concentration or less.

Examples of the salt of erythorbic acid include, but are not limited to, sodium salt, potassium salt, ammonium salt and the like.

The content of N-acetyl-L-cysteine and erythorbic acid or a salt thereof can be appropriately set according to the content of the galvanic acid or the gallic acid-binding compound, but the molar concentration is equal to or higher than that of the galvanic acid or the gallic acid-binding compound, respectively. It is preferably 1.5 times molar concentration or more, more preferably 2.5 times molar concentration or more, and 5 times molar concentration or less, preferably 4.5 times molar concentration or less, more preferably 4 times molar concentration or less, and more. Preferably, the molar concentration is 3 times or less.
Further, the content of erythorbic acid and its salt, and N-acetyl-L-cysteine is preferably equal to or higher than the equimolar concentration and 5 times the molar concentration or less, more preferably 2 times the molar concentration with respect to the nitrites. The following can be mentioned.

The content of sulfites, N-acetyl-L-cysteine and erythorbic acid or a salt thereof may be the same concentration or different concentrations as long as the stability of the liquid preparation can be improved.

The liquid preparation of the present invention can be used as a food, a pharmaceutical product, a protective agent for cells or organs, etc., depending on the use of the gallic acid or the gallic acid-binding compound contained therein.
When the liquid agent of the present invention is used as a pharmaceutical product, one or more pharmaceutically acceptable excipients such as preservatives, viscosity modifiers, tonicity agents, buffers, absorption enhancers, surfactants and stabilizers are used. It may contain agents, moisture proofing agents, solubilizing agents and the like. When used as food, one or more sweeteners, colorants, preservatives, thickeners, color formers, bleaching agents, fungicides, bitterness agents, brighteners, flavors, acidulants, softeners, seasonings. It may contain agents, emulsifiers, pH regulators, leavening agents, nutritional enhancers and the like. When used as a cell or organ protectant, it may contain a pH regulator, isotonic agent, leavening agent, chelating agent and cryoprotectant.

When the liquid preparation of the present invention is used as a pharmaceutical product, the gallic acid or the gallic acid-binding compound itself can be a medicinal ingredient, but it is also possible to contain any medicinal ingredient. Examples of pharmaceuticals include antipyretic drugs, analgesics, anti-inflammatory drugs, anti-rheumatic drugs, hypnotics, sedatives, anti-anxiety drugs, anti-psychiatric drugs, antidepressants, anti-epileptic drugs, Parkinson's disease therapeutic drugs, and cerebral circulation metabolism. Improving drug, muscle relaxant, autonomic nervous system agent, anti-disease drug, migraine treatment drug, cardiotonic drug, anti-angina drug, β-blocker, Ca antagonist, anti-arrhythmic drug, diuretic drug, antihypertensive drug, anti Allergic drugs, bronchial dilators, asthma remedies, antitussives, sputum remedies, digestive ulcer remedies, gout remedies, dyslipidemia drugs, diabetes drugs, hormone preparations, osteoporosis drugs, anesthesia, antineoplastic agents, antibacterial drugs , Antiviral drugs, antiparasitic drugs, antigenic insects, immunosuppressive drugs and drugs classified as vaccines.

The liquid preparation of the present invention uses a known method to prepare as described above-mentioned various substances in addition to asbestosic acid or an asbestosic acid-binding compound, sulfites, N-acetyl-L-cysteine and erythorbic acid or a salt thereof, if necessary. It can be prepared by dissolving it in a liquid such as water or a buffer solution. The liquid can be appropriately selected depending on the intended use, and examples thereof include water, a phosphate buffer solution, a citric acid buffer solution, a Tris buffer solution, a physiological saline solution, and various culture solutions such as Minimum Essential Medium (MEM).

The liquid preparation of the present invention can be used as a food, cosmetic, or pharmaceutical product depending on the use of the gallic acid or the gallic acid-binding compound contained therein.
When the liquid agent of the present invention is used as a food, one or more sweeteners, coloring agents, preservatives, thickeners, coloring agents, bleaching agents, fungicides, emulsifiers, swelling agents, seasonings, acidulants, bitter tastes. It may contain an agent, a brightener, a nutritional enhancer, a fragrance, a pH adjuster and the like. When used as cosmetics, one or more oily components, surfactants, moisturizers, polymer substances, thickeners, solvents, colorants, fragrances, UV protection agents, antibacterial agents, chelating agents, pH adjusters. , Physiologically active ingredients and the like may be contained. When used as a pharmaceutical product, one or more pharmaceutically acceptable excipients such as preservatives, viscosity modifiers, tonicity agents, absorption promoters, surfactants, stabilizers and moisture proofing agents. , Dissolving aids and the like may be contained.

When the liquid preparation of the present invention is used as a pharmaceutical product, the gallic acid or the gallic acid-binding compound itself can be a medicinal ingredient, but it is also possible to contain any medicinal ingredient. Examples of pharmaceuticals include antipyretic drugs, analgesics, anti-inflammatory drugs, antibody rheumatism drugs, hypnotics, analgesics, anti-anxiety drugs, antipsychotic drugs, antidepressants, antiepileptic drugs, Parkinson's disease therapeutic drugs, and cerebral circulation metabolism. Improvement drug, muscle relaxant, autonomic nervous system agent, anti-disease drug, migraine drug, cardiotonic drug, anti-angina, β-blocker, Ca antagonist, anti-arrhythmic drug, diuretic drug, antihypertensive drug, anti Allergic drugs, bronchial dilators, asthma remedies, antitussives, sputum remedies, digestive ulcer remedies, gout remedies, dyslipidemia drugs, diabetes drugs, hormone preparations, osteoporosis drugs, anesthesia, antineoplastic agents, antibacterial drugs , Antiviral drugs, antiparasitic drugs, antigenic insects, immunosuppressive drugs, drugs classified into vaccines.

The liquid preparation of the present invention uses a known method, and in addition to ascetic acid or an asbestosic acid-binding compound, sulfites, erythorbic acid or a salt thereof, N-acetyl-L-cysteine, and various substances described above, if necessary. Can be prepared by dissolving in a liquid such as water or a buffer solution. The liquid can be appropriately selected depending on the intended use, and examples thereof include water, a phosphate buffer solution, a citric acid buffer solution, a Tris buffer solution, a physiological saline solution, and various culture solutions such as Minimum Essential Medium (MEM).

Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited thereto.

A formulation containing potassium disulfurous acid as sulfites was prepared as described in (1) below. As in Patent Document 2 described above, potassium sulfite is known to suppress the oxidation of L-ascorbic acid and enhance the stability of polyphenols. Therefore, polyphenols (gallate, epigallocatechin gallate, or ethyl gallate) are added to each formulation as described in (2) to (4) below, and the stability of each formulation is used as an index for each formulation. The effect was evaluated.

(1) Preparation of formulation In 50 mM Tris (hydroxymethyl) aminomethane (Tris) -HCl buffer (pH 7.6), potassium disulfate (Potassium methabilphite: PMB), L-ascorbic acid (Vitamin C: VC), sodium erythorbate. (Sodium erythorbate: SE), N-acetyl-L-cysteine (N-acetyll-L-cysteine: NAC) were added alone or in combination to dissolve them, and these were compared with Comparative Examples (Formulations 2, 3, 4, and). 5) and Example (Prescription 6). Moreover, 50 mM Tris-HCl buffer (pH 7.6) was used as a control (formulation 1). The specific composition is as shown in Table 1.

(2) Evaluation of stability of each formulation containing gallic acid Prepare a solution containing gallic acid (GA), which is a polyphenol, so that the final concentration of each formulation is 0.44 mM, and prepare a solution at 4 ° C or 25. These stability was evaluated by storing in an incubator set at ° C. Stability evaluation was performed before storage (Day 0), on the 4th day of storage (Day 4), on the 7th day of storage (Day 7), on the 14th day of storage (Day 14), and on the 35th day of storage (Day 35). The visual judgment and the quantitative value of the galloyl group were used as an index.

The quantification of the galloyl group was carried out by the iron tartrate method described below. First, in 0.1 M 2- (N-morpholino) ethanesulphonic acid (: MES) buffer (pH 5.5), the final concentration was 12.5 mg / mL sodium dodecyl sulfate and 2.5 mg / mL sodium tartrate. Potassium tetrahydrate and 0.5 mg / mL iron (II) sulfate heptahydrate were gently dissolved, and this was used as an iron tartrate reagent. Next, a solution was prepared by adding ethyl gallate to a final concentration of 15.6 μM, 31.3 μM, 62.5 μM, 125 μM, and 250 μM in 0.1 M MES buffer (pH 5.5), respectively. , These were used as standard solutions for calibration curves. 20 μL of iron tartrate reagent was taken and 180 μL of each formulation containing 0.1 M MES buffer (pH 5.5) (blank), calibration curve standard solution, or gallic acid was added thereto. Further, 12 μL of 2M Tris was added and mixed gently. The absorbance of this reaction solution was measured at wavelengths of 520 nm and 660 nm, and the difference in absorbance at these two wavelengths was determined. After preparing a calibration curve from the difference in the absorbance of the standard solution for the calibration curve, the concentration obtained by the calibration curve method from the difference in the absorbance of each prescription was used as the quantitative value of the galloyl group. The measurement was performed 3 times for each prescription, and the quantitative value was shown by the average value ± standard deviation of the galloyl group concentration.

First, the results of visually determining the presence or absence of coloration of the solution are shown in FIGS. 1, 2, 2, and 3.
At a storage temperature of 4 ° C., coloring was confirmed by the 35th day of storage in Formulations 1 to 5, but in Formulation 6 containing potassium disulfurous acid, sodium erythorbate, and N-acetyl-L-cysteine, the 35th day. No coloring was confirmed until (Fig. 1 and Table 2). Similarly, even at a storage temperature of 25 ° C., coloring was confirmed in Formulations 1 to 5 by the 14th day of storage, but coloring was not confirmed in Formulation 6 of the present invention (FIGS. 2 and 3).

Next, the quantification results of the galloyl group are shown in FIGS. 3 and 4. Similar to coloring, in Formulations 1 to 5, the galloyl group concentration was significantly reduced from the concentration before storage, but in Formulation 6 of the present invention, it was found that the galloyl group concentration maintained the concentration before storage during the storage period. (Fig. 3 and Fig. 4). In particular, in the combined use of potassium disulfurous acid and L-ascorbic acid described in Patent Document 2 (Formulation 2), the galloyl group concentration decreased to 42.3% before storage on the 35th day of storage at 4 ° C. The formulation 6 of the present invention surpassed it and maintained 90.5% before storage. Further, on the 14th day of storage at 25 ° C., the galloyl group concentration of Formulation 2 decreased to 11.7% before storage, and Formulation 6 of the present invention maintained 96.5% before storage.

Based on the results of the above visual determination of coloring and quantification of galloyl groups, the formulation combining the three of potassium disulfurous acid, sodium erythorbate, and N-acetyl-L-cysteine shown in formulation 6 of the present invention is based on potassium disulfurous acid. The longest period of time compared to any combination of L-ascorbic acid (Patent Document 2 above), potassium disulfate alone, and N-acetyl-L-cysteine or a combination of sodium erythorbate and potassium disulfate. The effect of suppressing coloring and reduction of galloyl groups was confirmed, and it was considered that Formulation 6 of the present invention had the best stabilizing effect of polyphenol. In Formulations 3, 4, and 5 at a storage temperature of 4 ° C., it was confirmed that the strong coloring confirmed in a short period of time tended to be attenuated during the subsequent storage, which is the bleaching effect of potassium disulfurous acid. The quantitative value of the galloyl group at this time was different from the visual result, and a downward tendency was confirmed.

(3) Evaluation of stability of each prescription containing epigallocatechin gallic acid Epigallocatechin gallic acid, which is a polyphenol so that the final concentration of each prescription shown in Table 1 is 0.44 mM, as in the case of the above-mentioned epigallocatechin gallic acid. The stability of the solution to which gallocatechin gallate (EGCG) was added was evaluated. The stability evaluation was performed by visual inspection of coloring and the measured absorbance value as indexes, and the absorbance measurement was performed by measuring the absorbance at wavelengths of 400 nm and 660 nm, and comparatively evaluating by the difference between the absorbances of these two wavelengths.

The results of visually determining the presence or absence of coloration of the solution are shown in FIGS. 5, 6, 4, and 5. At the storage temperature of 4 ° C., coloring was confirmed in Formulations 1 to 5 by the 14th day of storage, but in Formulation 6, coloring was not confirmed until the 28th day (FIGS. 5 and 4). Similarly, at a storage temperature of 25 ° C., coloring was confirmed by the 7th day of storage in the formulations 1 to 5, but no coloring was confirmed in the 7th day of storage in the formulation 6 (FIGS. 6 and 5). ). In addition, when the absorbance was measured, a result correlating with coloring was obtained, and the absorbance increased in Formulations 1 to 5, but in Formulation 6 of the present invention, the absorbance hardly increased or the absorbance increased from Formulations 1 to 5. Delayed (FIGS. 7 and 8).

Therefore, the formulation 6 of the present invention, which is a combination of three types of potassium disulfurous acid, sodium erythorbate, and N-acetyl-L-cysteine, is any of formulations 1 to 5 as in the above-mentioned evaluation using gallic acid. It was clarified that the solution containing epigallocatechin gallic acid has an effect of preventing coloration for the longest period of time.

(4) Evaluation of stability of each formulation containing ethyl gallate As in the case of the above-mentioned gallate and epigallocatechin gallate, gallate so as to have a final concentration of 0.44 mM for each formulation shown in Table 1. The stability of the solution to which ethyl (Ethyl gallate: EG) was added was evaluated. The stability evaluation was based on the visual judgment of coloring and the measured value of absorbance.

The results of visually determining the presence or absence of coloration of the solution are shown in FIGS. 9, 10, 6, and 7. At a storage temperature of 4 ° C., prescriptions 1, 3, and 4 were confirmed to be colored by the 14th day of storage, but formulations 2, 5, and 6 were not confirmed to be colored even on the 56th day of storage (prescriptions 2, 5, and 6). 9 and 6). Further, at a storage temperature of 25 ° C., weak coloring was confirmed by the 14th day of storage in the formulations 1 to 5, but no coloring was confirmed by the 14th day of storage in the formulation 6 of the present invention (FIG. 10). And Table 7). In addition, as a result of the absorbance measurement, an increase in the absorbance that was substantially correlated with the coloring was confirmed, and no increase in the absorbance was observed only in the formulation 6 of the present invention in which the coloring was not confirmed (FIGS. 11 and 12).

From the above, especially from the result of the storage temperature of 25 ° C., the formulation of the present invention in which potassium disulfurous acid, sodium erythorbate, and N-acetyl-L-cysteine are combined can be used to color a liquid containing ethyl gallate. It has been shown to prevent for the longest period of time. Furthermore, considering the results of the stability evaluation of the formulation containing the above-mentioned gallic acid and epigallocatechin gallic acid, the antioxidant effect of potassium disulfurous acid is the best at both the storage temperature of 4 ° C and 25 ° C. It was considered effective to combine erythorbic acid or a salt thereof and N-acetyl-L-cysteine for long-term maintenance.

Claims (8)

A liquid preparation containing gallic acid or a gallic acid-binding compound, and sulfites, erythorbic acid or a salt thereof, and N-acetyl-L-cysteine. The liquid preparation according to claim 1, which contains gallic acid or a gallic acid-binding compound in an equimolar concentration or higher. The liquid preparation according to claim 1 or 2, which contains N-acetyl-L-cysteine and erythorbic acid or a salt thereof in an equimolar concentration or more and a 5-fold molar concentration or less, respectively, with gallic acid or a gallic acid-binding compound. Gallic acid or a gallic acid-binding compound is gallic acid or a salt thereof, gallic acid or a salt thereof, a lower alkyl ester of gallic acid, epigallocatechin gallate, epicatechin gallate, pentagalloylglucose, glucogalin, tannic acid, galloyl. Select from bergenin, galloylalbutin and N2, N6-bis [N2, N6-bis (3,4,5-trihydroxybenzoyl) -licyl] -N- (2-aminoethyl) -lysineamide epigallocatechin gallate The liquid agent according to any one of claims 1 to 3, which is one or more of the above-mentioned liquid agents. A method for stabilizing a gallic acid or a gallic acid-binding compound in a liquid preparation, which comprises a step of adding sulfites, N-acetyl-L-cysteine and erythorbic acid or a salt thereof. The method according to claim 5, wherein the sulfites are added so as to contain gallic acid or a gallic acid-binding compound in an equimolar concentration or higher. The method according to claim 5 or 6, wherein N-acetyl-L-cysteine and erythorbic acid or a salt thereof are added so as to contain gallic acid or a gallic acid-binding compound in an equimolar concentration or more and a 5-fold molar concentration or less, respectively. A stabilizer for a liquid preparation containing gallic acid or a gallic acid-binding compound containing sulfites, N-acetyl-L-cysteine and erythorbic acid or a salt thereof as active ingredients.

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