TW202000193A - External-use composition - Google Patents

Abstract

The present invention provides an external-use composition including ascorbic acid or the like. More preferably, the present invention provides an external-use composition including ascorbic acid or the like the deposition of which is suppressed under a low-temperature storage condition. This external-use composition contains the following components: (A) at least one selected from the group consisting of ascorbic acid, derivatives thereof, and salts thereof; (B) an edetic acid salt; (C) erythritol; (D) a heparin-like substance; and (E) water.

Description

Topical composition

The present invention relates to an external composition containing ascorbic acids. More preferably, it relates to an ascorbic acid-containing external composition in which precipitation under low-temperature storage conditions is suppressed. In addition, the present invention relates to a method for suppressing precipitation under low-temperature storage conditions for an external composition containing ascorbic acid.

Ascorbic acid or its salts are used as antioxidants (antioxidants) for the purpose of preventing oxidation of products due to their strong antioxidant effect. In addition, due to the inhibitory effect of melanin production (whitening effect) based on antioxidants It is widely used in cosmetics, topical medicines or topical medicines. In addition, many ascorbic acid derivatives with improved permeability to skin have also been developed.

It is known that although these ascorbic acids have relatively high solubility in water, they are difficult to dissolve in lower alcohols such as ethanol, and furthermore show poor solubility in polyhydric alcohols such as glycerin. In this way, ascorbic acids have a problem that their solubility is reduced by the solvent or the formulated component, and they are particularly likely to precipitate under low temperature conditions. However, although the applicant understands this situation, it has not yet proposed a problem or method for improving the precipitation of the ascorbic acid in the aqueous composition.

[Problems to be solved by the invention] The inventors and others have increasingly researched and found that the composition for external use in which ascorbic acid is dissolved in water together with edetate and erythritol, due to storage at a low temperature of 5°C, is White crystals precipitated within a short period of time, and storage stability was poor. In addition, this phenomenon also occurs when ascorbic acid is replaced with ascorbic acid derivatives.

Therefore, the subject of the present invention is to dissolve ascorbic acid, its derivatives or these salts (also collectively referred to as "ascorbic acids" in this specification) together with edetate and erythritol in water The composition for external use inhibits precipitation and improves storage stability. Specifically, an object of the present invention is to provide a composition for external use containing ascorbic acid, edetate, erythritol, and water, and the precipitation under low temperature conditions is suppressed, and has good storage stability. [Means to solve the problem]

In order to solve the above-mentioned problems, the present inventors have repeatedly conducted diligent research, and as a result, found that by preparing heparin-like substances in addition to ascorbic acid, edetate, erythritol, and water, precipitation under low temperature conditions Obviously suppressed, storage stability is improved. The present invention is based on the findings and has the following embodiments.

(I) External composition (I-1) A composition for external use containing the following components (A) to (E): (A) at least one selected from the group consisting of ascorbic acid, its derivatives, and these salts, (B) edetate, (C) erythritol, (D) Heparin-like substances, and (E) Water. (I-2) The composition for external use as described in (I-1), in which the component (A) is contained in a ratio of 0.01% by mass to 10% by mass in 100% by mass of the composition for external use. (I-3) The external composition according to (I-1) or (I-2), wherein the total amount is 0.5 parts by mass to 500 parts by mass relative to 100 parts by mass of the component (A) in the external composition The proportion of parts contains (D) component. (I-4) The composition for external use according to any one of (I-1) to (I-3), wherein the pH is in the range of 3 to 7. (I-5) The composition for external use according to any one of (I-1) to (I-4), which is a liquid or semi-solid composition. (I-6) The composition for external use according to any one of (I-1) to (I-5), which is a cosmetic, a pharmaceutical for external use, or a pharmaceutical for external use. (I-7) The composition for external use according to any one of (I-1) to (I-6), which is a composition in which the precipitation of crystals under storage at 5°C is suppressed.

(II) Methods for suppressing the formation of precipitates (II-1) A method of suppressing the formation of precipitates, which is a method of suppressing the formation of precipitates of an external composition containing the following components (A), (B), (C) and (E), including addition and mixing The following steps of (A) component to (E) component, and (A) component, (B) component, (C) component, (E) component and (D) component: (A) at least one selected from the group consisting of ascorbic acid, its derivatives, and these salts, (B) edetate, (C) erythritol, (D) Heparin-like substances, and (E) Water. (II-2) The method for suppressing the formation of precipitates according to (II-1), wherein the composition for external use contains the component (A) in a ratio of 0.01% by mass to 10% by mass in total. (II-3) The method for suppressing the formation of precipitates according to (II-1) or (II-2), wherein the total amount is 0.5 parts by mass to 100 parts by mass of the component (A) in the external composition The component (D) is formulated in a ratio of 500 parts by mass. (II-4) The method for suppressing the formation of precipitates according to any one of (II-1) to (II-3), including the step of adjusting the pH of the composition for external use to 3 to 7. (II-5) The method for suppressing the formation of precipitates according to any one of (II-1) to (II-4), wherein the composition is a liquid or semi-solid composition. (II-6) The method for suppressing the formation of precipitates according to any one of (II-1) to (II-5), wherein the composition is a cosmetic, an external pharmaceutical product, or an external pharmaceutical product. (II-7) The method for suppressing the formation of precipitates according to any one of (II-1) to (II-6), which is a method for suppressing the precipitation of crystals stored at 5°C. [Effect of invention]

According to the present invention, the external composition containing ascorbic acid, edetate, erythritol, and water can suppress the formation of precipitates under low temperature conditions. Therefore, according to the present invention, the ascorbic acid-containing composition can be provided with improved or improved storage stability at low temperatures.

(I) External composition The composition for external use of the present invention is characterized by containing the components (A) to (E) described below. (A) Ingredient: Ascorbic acid (a) Ascorbic acid The ascorbic acid used in the present invention is not particularly limited as long as it is used as a component of an external preparation in the field of cosmetics, pharmaceuticals, or external medicines. For example, L-ascorbic acid known as the common name vitamin C can be preferably cited.

(B) Ascorbic acid derivatives As the derivative of ascorbic acid, as with ascorbic acid, it may be any derivative of ascorbic acid used as a component of an external preparation for cosmetics, pharmaceuticals, or external medicines. Although not limited, preferably, ester derivatives or ether derivatives are exemplified. Specifically, examples of the ester derivatives of ascorbic acid include: ascorbic acid phosphate esters such as L-ascorbic acid monophosphate, L-ascorbic acid diphosphate, and L-ascorbic acid triphosphate; L-ascorbic acid palmitate, L-ascorbic acid Fatty acid esters of ascorbic acid such as isopalmitate, L-ascorbic acid stearate and L-ascorbic acid isostearate; L-ascorbic acid-2-sulfate. In addition, examples of the ether derivatives of ascorbic acid include alkyl ethers of ascorbic acid such as L-ascorbic acid methyl ether, L-ascorbic acid ethyl ether, L-ascorbic acid propyl ether, L-ascorbic acid butyl ether; L-ascorbic acid-2-glucoside, etc. Glucoside of ascorbic acid, etc. It is preferably an ester derivative or ether derivative which is water-soluble or highly water-soluble. Examples of the ester derivative or ether derivative include the phosphate ester of ascorbic acid and L-ascorbic acid-2-sulfate (the above is an ester derivative) Substance), L-ascorbic acid ether, L-ascorbic acid-2-glucoside (the above is an ether derivative).

(C) Salts of ascorbic acid or its derivatives Examples of salts of ascorbic acid or its derivatives include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as magnesium, calcium and barium; and metal salts such as polyvalent metal salts such as aluminum; ammonium and tricyclohexylammonium; Ammonium salts; and alkanolamine salts such as monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine and triisopropanolamine. Alkali metal salts such as sodium are preferred.

Preferred examples of ascorbic acids include, for example, L-ascorbic acid, L-ascorbic acid phosphate, L-ascorbic acid-2-sulfate, L-ascorbic acid-2-glucoside, ascorbic acid ether, and salts of these. When used as a component of a topical composition, L-ascorbic acid, L-ascorbic acid monophosphate, L-ascorbic acid-2-glucoside are particularly preferred in terms of high safety and high effect on skin or mucous membranes , Ascorbic acid ether and these salts.

The content of ascorbic acid in the external composition of the present invention can be selected from the range of 0.01% to 10% by mass with respect to the total amount of the external composition of 100% by mass. The ascorbic acid is preferably formulated in an amount of about 0.01% by mass or more for exerting an antioxidant effect, and is preferably formulated in an amount of about 3% by mass or more for exerting a melanin production inhibitory effect. In addition, as a content that can preferably obtain a precipitation inhibitory effect obtained by mixing heparin or the like described later, it is about 0.1% by mass or more, and preferably 0.3% by mass to 10% by mass, more preferably 1% by mass to 5% by mass.

(B) Ingredient: edetate The edetate salt is a pharmaceutically acceptable salt as long as it is an edetate salt used as a component of an external preparation for cosmetics, pharmaceuticals, or external medicines. Although not limited, for example, alkali metal salts such as sodium and potassium; alkaline earth metal salts such as magnesium, calcium, and barium; metal salts such as polyvalent metal salts such as aluminum; and ammonium salts such as ammonium and tricyclohexylammonium. Preferably, alkali metal salts such as disodium edetate or tetrasodium edetate; or alkaline earth metal salts such as disodium edetate and the like can be cited. Disodium edetate is preferred. Furthermore, these edetates also include hydrates (hydrates) such as edetate tetrasodium tetrahydrate. Disodium edetate is preferred. Disodium edetate is also known as sodium edetate, sodium ethylenediaminetetraacetate or sodium EDTA, and is used as a stabilizer, metal ion blocker, antioxidant, antibacterial in the field of cosmetics, pharmaceuticals or external medicines. Agents, preservatives or preservatives have been widely used since.

The content of the edetate in the external composition of the present invention can be selected and set from a range that allows formulation with respect to an external preparation for cosmetics, pharmaceuticals, or external medicines. Although not limited, for example, it can be selected from the range of 0.01% by mass to 0.5% by mass, preferably 0.01% by mass to 0.3% by mass, and more preferably 0.05% by mass to 0.2% by mass.

(C) Ingredient: erythritol Erythritol is a sugar alcohol known to have a moisturizing effect and an endothermic effect, and has been used as a component of external preparations for cosmetics, pharmaceuticals, or external medicines for cosmetics, pharmaceuticals, or external use of pharmaceuticals.

The content of erythritol in the composition for external use of the present invention can be selected and set from a range that allows the formulation of the external preparation for cosmetics, pharmaceuticals, or external preparations for pharmaceuticals. Although not limited, for example, it can be selected from the range of 0.01% by mass to 10% by mass, preferably 0.5% by mass to 5% by mass, and more preferably 1% by mass to 3% by mass.

(D) Ingredient: Heparin-like substance Heparin-like substances are previously known components that promote blood circulation and skin moisturizing effects, and are polysulfated mucopolysaccharides such as chondroitin polysulfate. It is preferable that the monosaccharides constituting mucopolysaccharide per molecule have an average of 0.5 to 5 molecules, and an average of 0.6 to 3 molecules of sulfate groups. Heparin-like substances also include, for example, heparin; and chondroitin sulfate D and chondroitin sulfate E-like chondroitin polysulfate. Among them, heparin-like substances (Heparinoid) included in the Japanese Pharmacopoeia Pharmaceutical Specifications can be preferably used.

The content of the heparin-like substance in the composition for external use of the present invention can be selected and set from a range that is allowable for formulation with respect to an external preparation for cosmetics, pharmaceuticals, or external preparations for pharmaceuticals. Although not limited, for example, it can be selected from the range of 0.01% by mass to 1% by mass, preferably 0.05% by mass to 0.5% by mass, and more preferably 0.05% by mass to 0.4% by mass.

In addition, although the heparin-like substance is not limited, it is preferably prepared in the range of 0.5 parts by mass to 500 parts by mass with respect to 100 parts by mass of (A) ascorbic acid formulated in the external composition of the present invention. More preferably, it is 1 to 50 parts by mass, and particularly preferably 3 to 20 parts by mass.

In addition, although the heparin-like substance is not limited, it is preferably formulated in the range of 10 parts by mass to 3000 parts by mass with respect to 100 parts by mass of (B) edetate compounded in the external composition of the present invention. It is more preferably 30 parts by mass to 1,000 parts by mass, and particularly preferably 50 parts by mass to 500 parts by mass.

Furthermore, although the heparin-like substance is not limited, it is preferably formulated in the range of 0.5 to 100 parts by mass relative to 100 parts by mass of (C) erythritol formulated in the external composition of the present invention. It is more preferably 2.5 to 25 parts by mass, and particularly preferably 2.5 to 20 parts by mass.

When the ratio of the heparin-like substance ((D) component) to the (A) component, (B) component, and/or (C) component is within the above range, the (A) component, (B) component, (( C) The storage stability of the aqueous composition of the component and the component (D) at low temperature is improved, and the precipitation of crystals (production of precipitates) generated when the component (D) is not blended can be significantly suppressed.

(E) Ingredient: Water The water is not particularly limited as long as it has a degree of purity or refined system that is generally used in accordance with the use of the external composition (cosmetics, pharmaceuticals, pharmaceuticals for external use). Specifically, ion-exchanged water, distilled water, purified water, sterilized water, and the like can be used without limitation. In terms of hygiene or storage stability, purified water, ion exchange water, and sterilized water can be preferably used. The amount of water blended is such that the entire composition will eventually be 100% by mass. Specifically, it is possible to select and adjust within the range that exerts the precipitation suppression effect of the present invention without impairing the shape of the composition for external use of the present invention. Although not limited, it can be formulated in a ratio of, for example, 10% by mass to 99.8% by mass, preferably 50% by mass to 99% by mass, and more preferably 70% by mass to 95% by mass.

Other ingredients The composition for external use of the present invention can be formulated into pharmaceuticals, external medicines, or cosmetics within a range that does not impair storage stability (precipitation suppression) as an effect of the present invention, and does not impair the effect of each formulated component in amount and quality. Well-known additives. Examples of the additives include bases, surfactants, tackifiers, preservatives, antioxidants, chelating agents, stabilizers, irritation reducers, colorants, and fragrances. In addition, in order to add other useful effects to the composition for external use of the present invention, medicines can be formulated within a range that does not impair the storage stability (suppression of precipitation) as the effect of the present invention and does not impair the effect of each formulated component. A well-known effective ingredient added to a product, an external product of a medical department, or a cosmetic. Examples of the active ingredient include anti-inflammatory agents, moisturizers, vitamins, astringents, antibacterial ingredients, peptides or derivatives thereof, amino acids or derivatives thereof, cell activation ingredients, and anti-aging ingredients (anti-wrinkle agents) , Blood circulation promoting ingredients, whitening ingredients, natural extracts, enzymes, fungicides, etc.

PH of external composition Although the pH of the composition for external use of the present invention is not limited, it is preferably adjusted to a range of pH 2 to 9. More preferably, it is in the range of pH 3-7. By adjusting to this pH range, a more stable composition for external use can be prepared. In addition, the adjustment of pH can also use organic acids (citric acid, lactic acid, acetic acid, tartaric acid, malic acid, succinic acid, oxalic acid, fumaric acid, gluconic acid, aspartic acid, etc.) according to conventional methods or Salts, inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, etc.) or their salts, inorganic salts (sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, etc.), or organic salts (monoethanolamine, PH adjusters such as triethanolamine and other amines).

Form of preparation The composition for external use of the present invention may be a substance containing the above-mentioned components (A) to (E), and as long as the effect of the present invention is not hindered, it may be used as a base commonly used in pharmaceuticals, external medicines or cosmetics Or a carrier, and optionally additives or useful ingredients are mixed together to prepare a pharmaceutical composition, a pharmaceutical external preparation, or a cosmetic external composition.

The external composition of the present invention has a liquid or semi-solid form. The liquid or semi-solid state refers to a state that has a liquid or semi-solid state at least in a state of low temperature (5°C) to normal temperature (25±5°C). Here, the semi-solid state refers to a state that flows due to its own weight. Examples of substances having a liquid or semi-solid form include solutions, colloidal solutions (sols, suspensions, or emulsions), gels (jel), and the like.

When the external composition of the present invention is a pharmaceutical product, the form of the preparation is not particularly limited, and examples thereof include liquids, suspensions, emulsions, creams, ointments, gels, liniments, and lotions. Agent. The pharmaceutical external composition is preferably used in the form of a liquid, emulsion, or gel, and more preferably used in the form of a liquid or gel. These preparations can be manufactured according to the method described in the 17th revised Japanese Pharmacopoeia General Rules for Preparations.

In the case where the external composition of the present invention is an external medicine or cosmetic, the form is not particularly limited, and examples include basic cosmetics such as lotions, lotions, creams, beauty liquids, hand creams, and body lotions. Or medicinal cosmetics.

Manufacturing method The method for preparing the composition for external use of the present invention is not particularly limited, and it can be prepared according to the conventional method according to the type or use of the composition for external use (medicinal products, external medicines, cosmetics) and its shape. Specifically, for example, the above-mentioned (A) component to (E) component or, if necessary, other than these, general various components necessary for preparing an external composition can be appropriately selected and mixed, and prepared by a conventional method.

The external composition thus produced is filled and contained in a container. The shape of the container may be any shape as long as it can contain a liquid or semi-solid composition, and can be appropriately selected according to its form, use, and method of use (administration method). Although not limited, as an example of the container, a bottle container (rolling container, bottle container with a sponge-like coating member at the head, a jar container), a pump spray container, a pump spray container, an aerosol can be exemplified Use containers, and tube containers. The precipitation of the external composition of the present invention contained in a container under low-temperature conditions is significantly suppressed. For example, when stored at 5° C. for 2 days, the formation of precipitates is suppressed compared to the external composition without the component (D).

How to use The application amount or usage of the external composition of the present invention in the outer skin is not particularly limited, and it can usually be applied to the outer skin such as skin several times a day in an appropriate amount, for example, by applying it. Examples of uses of the external composition of the present invention include medical uses (treatment, improvement), skin care uses, etc., but the use is not particularly limited to these uses. The composition for external use of the present invention is aimed at moisturizing, anti-inflammation, and care (moisturizing) of traces (scars, scalds, acne marks, pregnancy lines) remaining on the skin to make it unobtrusive, and for the purpose of prevention of scarring, etc. Better use.

(II) Methods for suppressing the formation of precipitates The present invention is a method for suppressing the formation of precipitates during low-temperature storage of the external composition containing (A) ascorbic acid, (B) edetate, (C) erythritol, and (E) water. The method can be carried out by placing (A) to (C) components of the external composition in the presence of (E) and (D) a heparin-like substance in a coexisting state. This coexistence state can be easily formed by adding and mixing the (D) component when manufacturing the external composition containing the (A) component-(C) component and (E) component. That is, by preparing (D) component when manufacturing an external composition containing (A) component (C) component and (E) component, the external use containing (A) component (C) component and (E) component can be suppressed Precipitation of the composition under low temperature storage.

The "low-temperature storage" referred to in the present invention refers to storage at rest for 2 days or more under normal pressure at 5°C. The so-called "inhibition of the formation of precipitates at low temperature storage" refers to the storage of at least 2 days at least 5 days under normal pressure, and the combined use of (D) heparin-like substances to suppress the content of (A) ascorbic acid , (B) edetate, (C) erythritol, and (E) the formation of possible precipitates in the external composition of water. Furthermore, the suppression includes not only the case of completely inhibiting (preventing) the formation of precipitates, but also the case of delaying the generation of precipitates. As for whether the formation of precipitates is suppressed, as shown in Experimental Example 1 to be described later, it can be evaluated by including (A) ascorbic acid, (B) edetate, (C) erythritol, (D) Heparin-like substances and (E) the external composition of water (test sample) and the sample obtained by removing (D) heparin-like substance from the test sample as a control sample at least at normal pressure 5 Store at room temperature for 2 days or longer, and compare the formation of precipitates between the two. When the formation of precipitates of the test sample is suppressed compared with the control sample, it can be determined that the method of the present invention has been performed on the test sample. In addition, instead of "standing and storing for more than 2 days under normal pressure at 5°C", the accelerated test considered to be equivalent to it, the generation of precipitates in the test sample is suppressed compared to the control sample In the case of, the same can be judged.

The types of (A) component, (B) component, (C) component, (D) component, and (E) component used in the method of the present invention, or their blending ratios, and external compositions containing these objects such as ( As described in I), it can be directly used in the present invention. [Example]

Hereinafter, the configuration and effects of the present invention will be described in detail with examples. However, this example is only an example, and the present invention is not limited to these examples. In the following examples, unless otherwise mentioned, "%" means "mass %" and "part" means "mass part". In addition, as long as it is not specifically mentioned, the manufacture and experiment can be carried out under normal pressure and normal temperature conditions.

Experimental Example 1 Storage stability test The components shown in Table 1 were measured, stirred and dissolved to prepare an aqueous composition (Example 1 and Example 2, Comparative Example 1 and Comparative Example 2). Each of these was filled into a transparent glass bottle (with a lid), and the test sample immediately after preparation was visually observed for the presence or absence of precipitation. Then, these were stored in a dark place at 5°C for 2 days, and the presence or absence of precipitation after storage was visually observed.

*5℃2日後的評價Table 1 also shows the results. FIGS. 1(A) and 1(B) show images of the appearance of the test sample (Example 1 and Example 2, Comparative Example 1 and Comparative Example 2) immediately after preparation and after storage. . In addition, FIG. 2 shows an image of the appearance of the sample to be tested (Example 3) after storage. [Table 1]

*Evaluation after 2 days at 5℃

From this result, it can be seen that by further formulating the (D) component in the liquid or semi-solid composition containing the (A) component, (B) component, (C) component and (E) component, it can be stored under low temperature conditions The stability is improved and the formation of precipitates is suppressed.

Example 6 Liquid preparation (pH 3.6) An aqueous solution-like composition containing the following formulation and having suppressed precipitation under low temperature conditions was prepared. (Formulation) L-ascorbic acid 2-glucoside 2.0 (mass%) Disodium edetate 0.1 Erythritol 3.0 Heparin-like substances 0.3 1,3-Butanediol 8.0 1,2-pentanediol 5.0 Glycerin 3.0 Phenoxy Ethanol 0.4 Citric acid, appropriate amount of sodium citrate, appropriate amount of purified water, remaining part, total amount 100.0% by mass

Example 7 Gel agent (pH 6.9) A gel-like composition containing the following formulation and having precipitation suppressed under low temperature conditions was prepared. (Formulation) L-ascorbic acid 2-glucoside 2.0 Disodium edetate 0.1 Erythritol 2.0 Heparin-like substances 0.1 Isopropyl methyl phenol 0.1 Tocopheryl acetate 0.1 1,2-pentanediol 3.0 1,3-butane Glycol 5.0 Carboxyvinyl polymer 0.7 Hydroxypropyl methylcellulose 0.5 Methyl polysiloxane 2.6 Silicic anhydride 0.5 (Dimethicone/Vinyl Dimethicone) Cross-linked polymer/Dimethicone 0.5 Polysorbate 80* 1.0 Polyoxyethylene polyoxypropylene decyl myristyl ether 0.5 Paraben methyl ester 0.1 Citric acid amount Sodium citrate amount Potassium hydroxide amount Refined water Total remaining amount 100.0 mass % * Polyoxyethylene sorbitan monooleate (20E.0.)

no

1(A) and 1(B) show the results of Experimental Example 1. 1(A) shows an image of the appearance of each test sample (Example 1 to Example 2 and Comparative Example 1 to Comparative Example 2) immediately after preparation (before low temperature storage), and FIG. 1(B) shows Images of the appearance of each test sample (Example 1 to Example 2 and Comparative Example 1 to Comparative Example 2) after low temperature storage (2 days at 5°C). 2 is an image showing the appearance of Experimental Example 3 after low-temperature storage (2 days at 5° C.).

Claims (5)

A composition for external use, containing the following components A to E: Component A: at least one selected from the group consisting of ascorbic acid, its derivatives, and these salts, Component B: edetate, Component C: erythritol, Component D: Heparin-like substances, and E component: water. The composition for external use as described in item 1 of the scope of patent application, wherein component A is contained in a proportion of 0.01% by mass to 10% by mass out of a total of 100% by mass of the composition for external use. The composition for external use according to item 1 or 2 of the scope of patent application, wherein component D is contained in a ratio of 0.5 to 500 parts by mass relative to the total amount of component A in the external composition is 100 parts by mass. The composition for external use according to any one of items 1 to 3 of the patent application scope is a pharmaceutical product or a product of the Ministry of Medicine. A method for suppressing the formation of precipitates includes the steps of adding and mixing the following components A to E, and coexisting components A, B, C, E, and D: Component A: at least one selected from the group consisting of ascorbic acid, its derivatives, and these salts, Component B: edetate, Component C: erythritol, Component D: Heparin-like substances, and E component: water.

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