JP7321680B2 - external composition - Google Patents

Description

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

Ascorbic acid or its salt is used as an antioxidant (antioxidant) for the purpose of preventing oxidation of the product itself due to its strong antioxidant effect. Therefore, it has been widely used in cosmetics, topical drugs, and topical quasi-drugs. Many ascorbic acid derivatives with enhanced skin permeability have also been developed.

These ascorbic acids are known to have relatively high solubility in water, but are difficult to dissolve in lower alcohols such as ethanol, and even less soluble in polyhydric alcohols such as glycerol. . As described above, ascorbic acids have the problem that their solubility decreases depending on the solvent and ingredients, and they tend to precipitate especially under low temperature conditions. However, to the applicant's knowledge, the problem of precipitation in such an aqueous composition of ascorbic acids, or a method for improving the precipitation properties has not yet been proposed.

In daily research, the present inventors found that a topical composition in which ascorbic acid was dissolved in water together with edetate and erythritol turned white in a short period of 2 days by storage at a low temperature of 5°C. It was found that crystals precipitated and the storage stability was poor. Moreover, such a phenomenon similarly occurs even when ascorbic acid is replaced with an ascorbic acid derivative.

Therefore, the present invention provides a composition for external use in which ascorbic acid, derivatives thereof or salts thereof (herein, these are also collectively referred to as "ascorbic acids") are dissolved in water together with edetate and erythritol. An object of the present invention is to suppress it and improve its storage stability. Specifically, the object is to provide a composition for external use that contains ascorbic acids, edetate, erythritol, and water, yet is inhibited from precipitating under low-temperature conditions and has good storage stability. do.

The present inventors have made intensive studies to solve the above problems, and found that precipitation under low-temperature conditions can be achieved by blending a heparin-like substance in addition to ascorbic acids, edetate, erythritol, and water. It was found that it was significantly suppressed and the storage stability was improved.
The present invention is an invention completed based on such findings, and has the following embodiments.

(I) Composition for external use (I-1) Composition for external use containing the following components (A) to (E):
(A) at least one selected from the group consisting of ascorbic acid, derivatives thereof and salts thereof;
(B) edetate,
(C) erythritol,
(D) a heparinoid, and (E) water.
(I-2) The composition for external use described in (I-1), which contains the component (A) in a total amount of 0.01 to 10% by mass based on 100% by mass of the composition for external use.
(I-3) (I-1) or (I- 2) The external composition described in 2).
(I-4) The composition for external use according to any one of (I-1) to (I-3), which has a pH 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 topical composition according to any one of (I-1) to (I-5), which is a cosmetic, topical drug or topical quasi-drug.
(I-7) The composition for external use according to any one of (I-1) to (I-6), which is a composition in which crystal precipitation is suppressed when stored at 5°C.

(II) Method for Suppressing Precipitate Formation (II-1) A method for suppressing the formation of precipitates in an external composition containing the following components (A), (B), (C) and (E), comprising: A method for suppressing formation of precipitates, comprising a step of adding and mixing the (E) component and allowing the (A), (B), (C) and (E) components to coexist with the (D) component:
(A) at least one selected from the group consisting of ascorbic acid, derivatives thereof and salts thereof;
(B) edetate,
(C) erythritol,
(D) a heparinoid, and (E) water.
(II-2) The method for suppressing formation of precipitates according to (II-1), wherein the composition for external use contains the component (A) in a total amount of 0.01 to 10% by mass.
(II-3) Component (D) is blended in a total amount of 0.5 to 500 parts by mass with respect to 100 parts by mass of component (A) in the composition for external use, (II-1) or (II- 2) The method for suppressing formation of precipitates described in 2).
(II-4) The method for suppressing formation of precipitates according to any one of (II-1) to (II-3), which comprises adjusting the pH of the composition for external use to 3 to 7.
(II-5) The method for suppressing 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 formation of precipitates according to any one of (II-1) to (II-5), wherein the composition is a cosmetic, topical drug, or topical quasi drug.
(II-7) The method for suppressing formation of precipitates according to any one of (II-1) to (II-6), which is a method for suppressing crystal precipitation during storage at 5°C.

According to the present invention, an external composition containing ascorbic acids, edetate, erythritol, and water can be inhibited from forming deposits under low-temperature conditions. Therefore, according to the present invention, it is possible to provide the ascorbic acid-containing composition with improved or improved storage stability at low temperatures.

The results of Experimental Example 1 are shown. (A) Appearance of each test sample (Examples 1-2 and Comparative Examples 1-2) immediately after preparation (before low-temperature storage), (B) After low-temperature storage (5 ° C. 2 days) Each test sample ( 1 is an image showing the appearance of Examples 1 and 2 and Comparative Examples 1 and 2). 10 is an image showing the appearance of Experimental Example 3 after low-temperature storage (5° C. for 2 days).

(I) Composition for external use The composition for external use of the present invention is characterized by containing components (A) to (E) described below.
(A) component: ascorbic acids
(a) Ascorbic Acid The ascorbic acid used in the present invention is not particularly limited as long as it is used in the fields of cosmetics, pharmaceuticals, or quasi-drugs, particularly as a component of external preparations. For example, L-ascorbic acid, which is commonly known as vitamin C, can be preferably used.

(b) Derivatives of Ascorbic Acid Similar to ascorbic acid, ascorbic acid derivatives may be used as components of external preparations such as cosmetics, pharmaceuticals, or quasi-drugs. Ester derivatives or ether derivatives can be mentioned preferably, although not limited thereto. Specifically, ester derivatives of ascorbic acid include ascorbic acid phosphates such as L-ascorbic acid monophosphate, L-ascorbic acid diphosphate, and L-ascorbic acid triphosphate; Fatty acid esters of ascorbic acid such as palmitate, L-ascorbic acid isopalmitate, L-ascorbic acid stearate, and L-ascorbic acid isostearate; L-ascorbic acid-2-sulfate, etc. can be done. 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- Examples include glucosides of ascorbic acid, such as glucosides. Preferred are ester derivatives or ether derivatives that are water-soluble or highly water-soluble, such as ascorbic acid phosphate, L-ascorbic acid-2-sulfate (all ester derivatives), and ethyl L-ascorbate. Ethers, L-ascorbic acid-2-glucoside (above, ether derivatives) can be mentioned.

(c) Salts of ascorbic acid or derivatives thereof Salts of ascorbic acid or derivatives thereof include, 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; ammonium salts such as ammonium and tricyclohexylammonium; and alkanolamine salts such as monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine, and triisopropanolamine. be able to. Alkali metal salts such as sodium are preferred.

Preferred ascorbic acids include, for example, L-ascorbic acid, L-ascorbic acid phosphate, L-ascorbic acid-2-sulfate, L-ascorbic acid-2-glucoside, ascorbic acid ethyl ether, and their salt. L-ascorbic acid, L-ascorbic acid monophosphate, and L-ascorbic acid-2 are particularly preferred because of their high safety and high effect on skin or mucous membranes when used as a component of a composition for external use. - glucosides, ascorbic acid ethyl ether, and salts thereof.

The content of ascorbic acids in the topical composition of the present invention can be selected from the range of 0.01 to 10% by weight per 100% by weight of the total amount of the topical composition. About 0.01% by mass or more of ascorbic acids is preferable for exerting an antioxidant effect, and about 3% by mass or more is preferable for exerting a melanin production inhibitory effect. In addition, the content at which the effect of suppressing precipitation by blending heparin or a similar substance described later can be suitably obtained is about 0.1% by mass or more, preferably 0.3 to 10% by mass, more preferably 1 ~5% by mass can be exemplified.

Component (B): Edetate The salt of edetate is a pharmaceutically acceptable salt that can be used as a component of external preparations such as cosmetics, pharmaceuticals, or quasi-drugs. For example, but not limited to, 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; can be mentioned. Preferred are alkali metal salts such as disodium edetate and tetrasodium edetate; and alkaline earth metal salts such as calcium disodium edetate. Disodium edetate is preferred. These edetates also include hydrates (hydrate salts) such as edetate tetrasodium tetrahydrate. Disodium edetate is preferred. Disodium edetate, also known as sodium edetate, sodium ethylenediaminetetraacetate, or sodium EDTA, is used as a stabilizer, sequestering agent, antioxidant, antibacterial agent in the fields of cosmetics, pharmaceuticals, or quasi-drugs. It has been widely used in the past as an agent, antiseptic or preservative.

The content of the edetate salt in the composition for external use of the present invention can be selected and set within a range that is allowed for external use in cosmetics, pharmaceuticals, or quasi-drugs. Although not limited, it can be selected, for example, from the range of 0.01 to 0.5% by mass, preferably 0.01 to 0.3% by mass, more preferably 0.05 to 0.2% by mass.

(C) Ingredient: Erythritol Erythritol is a sugar alcohol known for its moisturizing and heat-absorbing properties. It has been used as an ingredient in external preparations for cosmetics, pharmaceuticals, and quasi-drugs for the purpose of moisturizing and improving the feeling of use. used for

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

(D) Component: Heparin-like substances Heparin-like substances are conventionally known components that promote blood circulation, moisturize skin, etc., and are polysulfated mucopolysaccharides such as chondroitin polysulfate. It is preferable to have an average of 0.5 to 5 molecules, more preferably an average of 0.6 to 3 molecules of sulfate groups per monosaccharide constituting the mucopolysaccharide. Heparin-like substances include, for example, heparin; and chondroitin polysulfates such as chondroitin sulfate D, chondroitin sulfate E, and the like. Among them, heparinoids (heparinoids) listed in the Japanese Pharmacopoeia Pharmaceutical Standards 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 within a range that is allowed for external use in cosmetics, pharmaceuticals, or quasi-drugs. Although not limited, it can be selected, for example, from the range of 0.01 to 1% by mass, preferably 0.05 to 0.5% by mass, more preferably 0.05 to 0.4% by mass.

The heparinoid is not particularly limited, but is preferably blended in the range of 0.5 to 500 parts by mass with respect to 100 parts by mass of (A) ascorbic acids blended in the composition for external use of the present invention. More preferably 1 to 50 parts by mass, particularly preferably 3 to 20 parts by mass.

The heparinoid is not particularly limited, but is preferably blended in the range of 10 to 3000 parts by mass per 100 parts by mass of edetate (B) blended in the composition for external use of the present invention. More preferably 30 to 1000 parts by mass, particularly preferably 50 to 500 parts by mass.

Further, the heparin analogue is not limited, but is preferably blended in the range of 0.5 to 100 parts by mass with respect to 100 parts by mass of (C) erythritol blended in the composition for external use of the present invention. More preferably 2.5 to 25 parts by mass, particularly preferably 2.5 to 20 parts by mass.

(A), (B), (C) and (D) because the ratio of the heparinoid (component (D)) to the components (A), (B) and/or (C) is within the above range The low-temperature storage stability of the aqueous composition containing the component is improved, and the precipitation of crystals (formation of precipitates) that can occur when the component (D) is not blended can be significantly suppressed.

(E) Component: Water Water generally has a degree of purity and purification that is used for external compositions (cosmetics, pharmaceuticals, quasi-drugs), as long as it is used. There are no particular restrictions. Specifically, ion-exchanged water, distilled water, purified water, sterilized water, and the like can be used without limitation. Purified water, ion-exchanged water, and sterilized water can be preferably used in terms of hygiene and storage stability. The amount of water to be blended is the amount that finally makes the total composition 100% by mass. Specifically, it can be selected and adjusted within a range in which the effect of suppressing precipitation of the present invention is exhibited without impairing the shape of the composition for external use of the present invention. Although not limited, it can be blended in a proportion of, for example, 10 to 99.8% by mass, preferably 50 to 99% by mass, more preferably 70 to 95% by mass.

Other Ingredients The composition for external use of the present invention contains pharmaceuticals and quasi-drugs in amounts and qualitative ranges that do not impair the effects of the present invention, i.e., storage stability (inhibition of deposition), and the effects of each ingredient. Alternatively, known additives that are added to cosmetics can be blended. Examples of such additives include bases, surfactants, thickeners, preservatives, antioxidants, chelating agents, stabilizers, irritation reducing agents, coloring agents, perfumes, and the like. In addition, in order to add other useful effects to the composition for external use of the present invention, the amount and quality of the composition does not impair the storage stability (precipitation suppression), which is the effect of the present invention, and the effects of each compounding component. Known active ingredients added to pharmaceuticals, quasi-drugs, or cosmetics can be blended within the range. Examples of such active ingredients include anti-inflammatory agents, moisturizers, vitamins, astringents, antibacterial ingredients, peptides or derivatives thereof, amino acids or derivatives thereof, cell activating ingredients, anti-aging ingredients (anti-wrinkle agents), and blood circulation promoting ingredients. , whitening ingredients, natural extracts, enzymes, fungicides and the like.

pH of topical composition
Although the pH of the composition for external use of the present invention is not limited, it is preferably adjusted in the range of pH 2-9. More preferably, the pH is in the range of 3-7. By adjusting the pH to such a range, a more stable composition for external use can be prepared. For adjustment of pH, if necessary, organic acids (citric acid, lactic acid, acetic acid, tartaric acid, malic acid, succinic acid, oxalic acid, fumaric acid, gluconic acid, aspartic acid, etc.) or salts thereof , inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, etc.) or salts thereof, inorganic salts (sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, etc.), or organic salts (monoethanolamine, pH adjusters such as amines such as triethanolamine can also be used.

Formulation Form The composition for external use of the present invention may consist of the above components (A) to (E). It can be mixed with a base or carrier that is usually used for , and if necessary, additives and useful ingredients to form an external composition for pharmaceuticals, quasi-drugs, or cosmetics.

The topical composition of the present invention has a liquid or semi-solid form. Liquid or semi-solid means that it has a liquid or semi-solid form at least at low temperature (5° C.) to room temperature (25±5° C.). Here, the term "semi-solid" means a form that flows under its own weight. Liquid or semi-solid forms include solutions, colloidal solutions (sols, suspensions and emulsions), and gels.

When the composition for external use of the present invention is a pharmaceutical, its formulation form is not particularly limited, and examples thereof include liquids, suspensions, emulsions, creams, ointments, gels, liniments, and lotions. be done. Pharmaceutical compositions for external use are preferably used in the form of liquids, emulsions or gels, more preferably liquids or gels. These formulations can be produced according to the methods described in the Japanese Pharmacopoeia General Rules for Preparations, 17th Edition.

When the composition for external use of the present invention is a quasi-drug or cosmetic, its form is not particularly limited. medicinal cosmetics and the like.

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 usual method based on the type and application (drugs, quasi-drugs, cosmetics) of the composition for external use and its shape. Specifically, for example, the above components (A) to (E), or, if necessary, in addition to these, the usual various components necessary for preparing a composition for external use are appropriately selected and blended, and the can be prepared.

The composition for external use thus produced is filled and contained in a container. The container may have any shape as long as it can contain a liquid or semi-solid composition, and can be appropriately selected according to its form, application, and method of use (administration method). Non-limiting examples of containers include bottle containers (roll-on containers, bottle containers having a spongy application member on the head, jar bottle containers), pump spray containers, pump discharge containers, containers for aerosol agents, and tube containers. etc. can be exemplified. The composition for external use of the present invention housed in a container is significantly inhibited from depositing under low temperature conditions. For example, when the composition is stored at 5°C for 2 days, the formation of precipitates is suppressed as compared with an external composition that does not contain the component (D).

Method of use and application The amount and method of application of the composition for external use of the present invention to the outer skin are not particularly limited, and usually, it can be used by applying, for example, applying an appropriate amount to the outer skin such as the skin several times a day. Applications of the composition for external use of the present invention include, but are not particularly limited to, medical applications (treatment/improvement), skin care applications, and the like. The composition for external use of the present invention is used for the purpose of moisturizing, anti-inflammatory, care (moisturizing) to make scars (scars, burn scars, acne scars, stretch marks) left on the skin less noticeable, and prevention of keloid formation. preferably used.

(II) Method for Suppressing Formation of Precipitates The present invention relates to a composition for external use containing (A) ascorbic acids, (B) edetate, (C) erythritol, and (E) water described above, and removes precipitates during low-temperature storage. is a method of suppressing the generation of The method can be carried out by coexisting components (A) to (C) of the composition for external use with (D) a heparinoid in the presence of (E). Such a coexisting state can be conveniently formed by adding and blending the component (D) when producing an external composition containing the components (A) to (C) and (E). That is, when manufacturing an external composition containing components (A) to (C) and (E), by blending component (D), external use containing components (A) to (C) and (E) Precipitation during low-temperature storage of the composition can be suppressed.

The term "low-temperature storage" as used in the present invention means stationary storage for two days or more under normal pressure conditions of 5°C. "Suppression of precipitate formation in low-temperature storage" means that (A) ascorbic acids, (B) edetate, (C) erythritol and (E ) It means that the formation of deposits that can occur with water-containing compositions for external use is suppressed by the combined use of (D) a heparinoid. Suppression includes both the case of completely inhibiting (preventing) the formation of precipitates and the case of delaying the formation of precipitates. Whether or not the formation of precipitates is suppressed can be determined by (A) ascorbic acids, (B) edetate, (C) erythritol, (D) heparinoids, and ( E) A topical composition containing water (test sample) and, as a control sample, a test sample from which (D) the heparin analogue was removed were stored under normal pressure conditions of 5°C for at least 2 days. , can be evaluated by comparing the formation of precipitates for both. If the formation of precipitates in the test sample is suppressed compared to 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 "stationary storage for 2 days or more under normal pressure 5 ° C condition", the generation of precipitates in the test sample is suppressed compared to the control sample by an accelerated test that can be regarded as equivalent conditions. can be determined in the same way.

Types and mixing ratios of components (A), (B), (C), (D), and (E) used in the method of the present invention, and topical compositions containing them are (I) , and can be used as it is in the present invention.

The configuration and effects of the present invention will be described in detail below with reference to examples, but the examples are examples and the present invention is not limited to these examples. In the following examples, "%" means "% by mass" and "parts" means "parts by mass" unless otherwise specified. In addition, unless otherwise specified, manufacturing and experiments were carried out under normal pressure and normal temperature conditions.

Experimental Example 1 Storage Stability Test The components shown in Table 1 were weighed, mixed with stirring and dissolved to prepare aqueous compositions (Examples 1 and 2, Comparative Examples 1 and 2). Each of these was filled in a transparent glass bottle (with a lid), and the presence or absence of precipitation was visually observed for the test sample immediately after preparation. 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.

The results are also shown in Table 1. FIG. 1 shows images of the appearance of the test samples (Examples 1 and 2, Comparative Examples 1 and 2) taken immediately after preparation and after storage. Further, FIG. 2 shows an image of the appearance after storage of the test sample (Example 3).

From this result, it was found that by adding component (D) to a liquid or semi-solid composition containing components (A), (B), (C) and (E), storage stability under low temperature conditions It can be seen that the properties are improved and the formation of precipitates is suppressed.

Example 6 Liquid (pH 3.6)
An aqueous composition having the following formulation and having suppressed precipitation under low-temperature conditions was prepared.
(Prescription)
L-ascorbic acid 2-glucoside 2.0 (mass%)
Disodium edetate 0.1
Erythritol 3.0
Heparinoid 0.3
1,3-butylene glycol 8.0
1,2-pentanediol 5.0
Glycerin 3.0
Phenoxyethanol 0.4
Citric acid Appropriate amount Sodium citrate Appropriate amount
Purified water Balance
Total amount 100.0% by mass

Example 7 Gel (pH 6.9)
A gel-like composition having the following formulation and having suppressed precipitation under low-temperature conditions was prepared.
(prescription)
L-ascorbic acid 2-glucoside 2.0
Disodium edetate 0.1
Erythritol 2.0
Heparinoid 0.1
Isopropylmethylphenol 0.1
Tocopherol acetate 0.1
1,2-pentanediol 3.0
1,3-butylene glycol 5.0
Carboxy vinyl polymer 0.7
Hydroxypropyl methylcellulose 0.5
Methylpolysiloxane 2.6
Silicic anhydride 0.5
(Dimethicone/vinyl dimethicone) crosspolymer/dimethicone 0.5
Polysorbate 80 ^* 1.0
Polyoxyethylene polyoxypropylene decyltetradecyl ether 0.5
Methylparaben 0.1
Citric acid Appropriate amount Na citrate Appropriate amount Potassium hydroxide Appropriate amount
Purified water Balance
Total amount 100.0% by mass

* Polyoxyethylene sorbitan monooleate (20E.0.)

Claims (4)

A composition for external use containing the following components (A) to (E),
External composition containing 2.5 to 20 parts by mass of component (D) in total with respect to 100 parts by mass of component (C) in the composition for external use:
(A) 1 to 5% by mass of at least one selected from the group consisting of ascorbic acid, ascorbic acid glucosides, and salts thereof;
(B) 0.05 to 0.2% by mass of edetate,
(C) 1 to 3% by mass of erythritol,
(D) 0.05 to 0.4% by mass of a heparin analogue, and (E) water. 2. The composition for external use according to claim 1, containing 3 to 20 parts by mass of component (D) in total per 100 parts by mass of component (A) in the composition for external use. 3. The composition for external use according to claim 1 or 2, which is a pharmaceutical or quasi-drug. A method for suppressing the formation of precipitates when a composition for external use containing the following components (A), (B), (C) and (E) is stored at normal pressure at 5°C for 2 days or more, comprising :
The method for suppressing formation of precipitates, comprising the step of adding and mixing the following components (A) to (E), and allowing the components (A), (B), (C) and (E) to coexist with the component (D):
(A) at least one selected from the group consisting of ascorbic acid, ascorbic acid glucosides and salts thereof;
(B) edetate,
(C) erythritol,
(D) a heparinoid, and (E) water.