JP7096285B2 - A method for suppressing discoloration of an external composition containing diphenhydramine or a salt thereof and ascorbic acid or a salt thereof. - Google Patents

Description

The present invention relates to a method for suppressing discoloration of an external composition containing diphenhydramine or a salt thereof and ascorbic acid or a salt thereof over time.

Since diphenhydramine or a salt thereof has a strong antihistamine effect, it is widely used as a pharmacologically active ingredient of pharmaceuticals and quasi-drugs in anticipation of antipruritic and antipruritic effects. Ascorbic acid or a salt thereof is widely used in pharmaceuticals, quasi-drugs, cosmetics, etc., with the expectation of anti-inflammatory effect, acne improving effect, whitening effect, anti-aging effect, antioxidant effect and the like. However, it is known that a preparation containing diphenhydramine or a salt thereof and ascorbic acid or a salt thereof may be discolored over time due to heat or light. If such discoloration occurs, the commercial value is lowered and it is not preferable. Therefore, a solution to the problem has been studied so far.

For example, for heat discoloration of diphenhydramine or a salt thereof, the oil and fat property is obtained by adding dibutylhydroxytoluene alone or in combination with dibutylhydroxytoluene and menthol to an oily ointment containing diphenhydramines. It is disclosed that discoloration of the ointment can be prevented (Patent Document 1).

Further, against discoloration of diphenhydramine or its salt due to light, the preparation containing diphenhydramine or its salt is stored in a light-shielding box or packaging container, and in the case of a solid preparation, a coating agent having a light-shielding agent. (Patent Documents 2 and 3), diphenhydramine salt is dispersed in an oil solution (Patent Document 4), and a specific polymer compound (Patent Document 5: Carboxymethylcellulose Calcium, Patent Document 6) is coated with diphenhydramine. : It is disclosed that discoloration of a preparation containing diphenhydramine or a salt thereof can be prevented by means such as adding (low swelling polymer and high swelling polymer) to formulate.

It is disclosed that discoloration of ascorbic acid or a salt thereof due to light can be prevented by adding it in combination with polymethacloyloxyethoxyphosphorylcholine (Patent Document 7). Further, it is disclosed that the heat-induced discoloration of ascorbic acid or a salt thereof can be suppressed over time at high temperatures by adding it in combination with synthetic stibnsite (Patent Document 8).

Regarding the problem of discoloration of ascorbic acid or a salt thereof over time, gelation using lecithin in combination with oxyresveratrol for the discoloration of ascorbic acid or a salt thereof (Patent Document 9). It is disclosed that discoloration can be prevented by using a skin external preparation (Patent Document 10) that does not contain polyhydric alcohol in combination with a sucrose fatty acid ester.

However, mucopolysaccharides have been effective as a means for suppressing discoloration of diphenhydramine or a salt thereof and ascorbic acid or a salt thereof over time, particularly discoloration over time due to heat and / or light. Was not known to.
Further, the methods disclosed in Patent Documents 1 to 10 suppress discoloration due to either light or heat, and no effective method for discoloration due to both light and heat has been known so far.

Japanese Unexamined Patent Publication No. 2006-28124 Japanese Unexamined Patent Publication No. 2007-284394 Japanese Unexamined Patent Publication No. 2003-300872 Japanese Patent Application Laid-Open No. 2003-37855 Japanese Unexamined Patent Publication No. 2007-291405 Japanese Unexamined Patent Publication No. 2004-107258 JP-A-2005-68115 Japanese Patent Application Laid-Open No. 2005-60239 Japanese Unexamined Patent Publication No. 2009-137874 Japanese Patent Application Laid-Open No. 2006-213738

An object of the present invention is to suppress discoloration over time, particularly discoloration over time due to heat and / or light, in an external composition containing diphenhydramine or a salt thereof and ascorbic acid or a salt thereof.

As a result of diligent research to solve the above problems, the present inventors have added mucopolysaccharides (preferably heparinoids, chondroitin sulfate or The coexistence of the salt, hyaluronic acid or a salt thereof, a hyaluronic acid derivative or a salt thereof, and dermatan sulfate or a salt thereof; particularly preferably a heparinoid) can suppress discoloration of the external composition over time. The present invention was completed.

Therefore, the present invention provides the following.
[1] In an external composition containing diphenhydramine or a salt thereof and ascorbic acid or a salt thereof, an external composition containing diphenhydramine or a salt thereof and ascorbic acid or a salt thereof in which one or more of mucopolysaccharides coexist. How to suppress discoloration of things.
[2] One or more mucopolysaccharides selected from the group consisting of heparinoids, chondroitin sulfate or salts thereof, hyaluronic acid or salts thereof, hyaluronic acid derivatives or salts thereof, and dermatan sulfate or salts thereof. The method according to [1].
[3] The method according to [1], wherein the mucopolysaccharide is one or more selected from the group consisting of a heparinoid and chondroitin sulfate or a salt thereof.
[4] The method according to any one of [1] to [3], wherein the external composition containing diphenhydramine or a salt thereof is an emulsion.
[5] The method according to any one of [1] to [3], wherein the external composition containing ascorbic acid or a salt thereof is a liquid preparation.
[6] Any of [1] to [5], wherein one or more of mucopolysaccharides coexist in an amount of 0.003 to 10 parts by weight based on 1 part by weight of diphenhydramine or a salt thereof and ascorbic acid or a salt thereof. The method described in Crab.
[7] The method according to any one of [1] to [6], wherein the discoloration is due to heat and / or light.

[8] A discoloration inhibitor for an external composition containing one or more of mucopolysaccharides as an active ingredient, diphenhydramine or a salt thereof, and ascorbic acid or a salt thereof.
[9] One or more mucopolysaccharides selected from the group consisting of heparinoids, chondroitin sulfate or salts thereof, hyaluronic acid or salts thereof, hyaluronic acid derivatives or salts thereof, and dermatan sulfate or salts thereof. The discoloration inhibitor according to [8].
[10] The discoloration inhibitor according to [8], wherein the mucopolysaccharide is one or more selected from the group consisting of a heparinoid and chondroitin sulfate or a salt thereof.
[11] The discoloration inhibitor according to any one of [8] to [10], wherein the external composition containing diphenhydramine or a salt thereof is an emulsion.
[12] The discoloration inhibitor according to any one of [8] to [10], wherein the external composition containing ascorbic acid or a salt thereof is a liquid preparation.
[13] Any of [8] to [12], wherein one or more of mucopolysaccharides coexist in an amount of 0.003 to 10 parts by weight based on 1 part by weight of diphenhydramine or a salt thereof and ascorbic acid or a salt thereof. Discoloration inhibitor described in Crab.
[14] The discoloration inhibitor according to any one of [8] to [13], wherein the discoloration is due to heat and / or light.

According to the method of the present invention, discoloration of an external composition containing diphenhydramine or a salt thereof and ascorbic acid or a salt thereof over time, particularly discoloration over time due to heat and / or light, can be suppressed.

Hereinafter, the present invention will be described in detail. It should be understood that the terms used herein are used in the meaning commonly used in the art unless otherwise noted.

The diphenhydramine contained in the external composition of the present invention is a known compound, and the salt of diphenhydramine can be used without particular limitation as long as it is pharmaceutically acceptable. Diphenhydramine or a salt thereof may be in the form of a hydrate.
Specific examples of diphenhydramine salts include organic acid salts (eg, acetates, trifluoroacetic acids, butyrates, palmitates, stearate and other monocarboxylates; fumarate, maleate, succinic acid). Polyvalent carboxylates such as salts and malonates; oxycarboxylates such as lactates, tartrates and citrates; organic sulfonates such as lauryl sulfates, methanesulfonates and toluenesulfonates; etc. ), Inorganic acid salts (eg, hydrochlorides, sulfates, nitrates, hydrobromates, phosphates, etc.), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine). , Salts with organic amines such as tripyridine, picolin, etc.), Salts with metals (eg, alkali metals such as sodium, potassium; alkaline earth metals such as calcium, magnesium; aluminum; salts with metals such as aluminum; etc.), Examples include ammonium salts.

The amount of diphenhydramine or a salt thereof to be blended in the external composition of the present invention is not particularly limited as long as it can exhibit a desired pharmacological action, but is usually 0.1% by weight or more, preferably 0.1% by weight or more, preferably with respect to the entire external composition. It is preferably 0.5% by weight or more, more preferably 1% by weight or more, and the upper limit of blending is usually 10% by weight or less, preferably 5% by weight or less, still more preferably 2% by weight or less.

The ascorbic acid contained in the external composition of the present invention is a known compound, and the salt of ascorbic acid can be used without particular limitation as long as it is pharmaceutically acceptable. Ascorbic acid or a salt thereof may be in the form of a hydrate.
Specific examples of the salt of ascorbic acid include a salt with an organic base (for example, a salt with a tertiary amine such as a trimethylamine salt, a triethylamine salt, a monoethanolamine salt, a triethanolamine salt and a pyridine salt, and a base such as arginine. Examples include salts with inorganic bases (eg, alkali metal salts such as ammonium salts, sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, etc.). Particularly preferable salts are sodium salt and potassium salt. Specific examples thereof include sodium ascorbic acid, sodium ascorbic acid monophosphate ester, sodium ascorbic acid diphosphate ester, sodium ascorbic acid triphosphate ester, and sodium ascorbic acid-2-sulfate ester.

As the ascorbic acid or a salt thereof contained in the external composition of the present invention, ascorbic acid or a salt thereof commercially available as a component of a skin external preparation in the fields of pharmaceuticals, quasi-drugs or cosmetics can be used. The blending amount of ascorbic acid or a salt thereof used in the present invention is not particularly limited as long as the effect of the present invention can be obtained, but is usually 0.1% by weight or more, preferably 0.5% by weight, based on the whole skin external preparation. % Or more, more preferably 1% by weight or more, and the upper limit of blending is usually 30% by weight or less, preferably 10% by weight or less, still more preferably 5% by weight or less.

The external composition containing diphenhydramine or a salt thereof and ascorbic acid or a salt thereof are discolored over time, particularly with heat and / or light, but the method for suppressing discoloration of the present invention is effective for mucopolysaccharides. It is characterized by being an ingredient.

Since mucopolysaccharide is known as a natural moisturizing factor for skin and has an excellent moisturizing effect, the external composition of the present invention can be obtained by coexisting mucopolysaccharide as an active ingredient of the discoloration suppressing method of the present invention. It is also expected that the product will have an excellent moisturizing effect.

Mucopolysaccharide is a polysaccharide containing amino sugar and uronic acid in its basic skeleton, and is obtained from animal tissues. Specific examples of mucopolysaccharides include heparinoids, chondroitin sulfate, dermatan sulfate, hyaluronic acid, heparan sulfate, heparin, keratan sulfate I and II, derivatives thereof, and salts thereof.

As the salts of heparinoids, chondroitin sulfate, dermatan sulfate, hyaluronic acid, heparan sulfate, heparin, keratan sulfate I and II and derivatives thereof, pharmaceutically and bioacceptable salts are preferable. For example, alkali metal salts such as sodium and potassium; alkaline earth metal salts such as magnesium and calcium; ammonium salts; alkanolamine salts such as monoethanolamine; and the like, preferably alkali metal salts such as sodium salts. Is.

The origin of the mucopolysaccharide used in the present invention is not particularly limited, and those that can be usually used in the fields of pharmaceuticals, quasi-drugs, and cosmetics can be used without particular limitation.
In the present invention, the mucopolysaccharide may be used alone or in any combination of two or more. If there is a commercially available mucopolysaccharide, the commercially available product may be used as it is.

In the composition of the present invention, the average molecular weight of the mucopolysaccharide is not particularly limited, but is usually 10 to 4 million, preferably 10 to 1.2 million, more preferably 50 to 1 million, and particularly preferably 5000 to 400,000. Is.

Specific examples of the mucopolysaccharide used in the present invention include heparin-like substances; chondroitin sulfate such as chondroitin sulfate and sodium chondroitin sulfate or salts thereof; dermatane sulfate such as dermatan sulfate and sodium dermatane sulfate or salts thereof; hyaluronic acid. , Hyaluronic acid such as sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate or salts thereof; hyaluronic acid such as acetyl hyaluronic acid, sodium acetyl hyaluronate, potassium acetyl hyaluronate, magnesium acetyl hyaluronate, calcium hyaluronate, etc. Examples thereof include acid derivatives or salts thereof; hyaluronic acid sulfate; heparin; keratane sulfates I and II; and the like, and mixtures thereof.

The mucopolysaccharide used in the present invention is preferably a heparin-like substance; chondroitin sulfate such as chondroitin sulfate and sodium chondroitin sulfate or a salt thereof; hyaluronic acid such as hyaluronic acid and sodium hyaluronate. Acids or salts thereof; hyaluronic acid derivatives such as acetyl hyaluronic acid and sodium acetyl hyaluronate or salts thereof; dermatan sulfate such as dermatan sulfate and sodium dermatan sulfate or salts thereof; are more preferably heparin-like substances, chondroitin sulfate, etc. Chondroitin sulfate such as sodium chondroitin sulfate or a salt thereof is particularly preferable, and examples thereof include heparin-like substances.

Here, the heparin-like substance means a general term for polysulfated mucopolysaccharides such as chondroitin polysaccharides, and an average of 0.5 to 5 molecules, preferably an average of 0.6 to 5 molecules per monosaccharide constituting the mucopolysaccharide. It preferably has three molecules of sulfate. More specifically, the heparinoid contains heparin, chondroitin sulfate D called chondroitin polysulfate, chondroitin sulfate E, and the like.
Heparinoids can also be obtained by sulfating mucopolysaccharides, or extracted and purified from the internal organs containing the bronchi of animals such as cattle and pigs using an aqueous carrier, and then sulfated as necessary. It can also be obtained by doing so. Since such a heparinoid has been developed as a raw material for pharmaceuticals and cosmetics, such a commercially available product can also be used.
In the composition for external use of the present invention, as the heparinoid, those contained in the Japanese Pharmacopoeia non-pharmacological standard are preferably used.

The amount of the mucopolysaccharide to be blended in the external composition of the present invention is not particularly limited as long as the effect of the present application can be obtained, but it is usually 0.005% by weight or more, preferably 0.01, based on the entire external composition. By weight% or more, more preferably 0.05% by weight or more, particularly preferably 0.1% by weight or more, and the upper limit of blending is usually 10% by weight or less, preferably 5% by weight or less, still more preferably 1% by weight or less. It is particularly preferable that the content is 0.5% by weight or less.

The weight ratio of diphenhydramine or a salt thereof and mucopolysaccharide in the external composition of the present invention is not particularly limited as long as the effect of the present application can be obtained, but mucopolysaccharide is usually 0 with respect to 1 part by weight of diphenhydramine or a salt thereof. It is preferably in the range of .005 to 10 parts by weight, preferably 0.01 to 5 parts by weight, more preferably 0.05 to 2 parts by weight, and particularly preferably 0.1 to 1 part by weight.

The weight ratio of ascorbic acid or a salt thereof and mucopolysaccharide in the external composition of the present invention is not particularly limited as long as the effect of the present application can be obtained, but mucopolysaccharide is usually used with respect to 1 part by weight of ascorbic acid or a salt thereof. Is preferably in the range of 0.003 to 10 parts by weight, preferably 0.005 to 1 part by weight, and more preferably 0.01 to 0.3 parts by weight.

The external composition of the present invention can be prepared in various forms depending on its use, for example, in the form of cream, milky lotion, gel milky lotion, lotion, beauty essence, lotion, ointment, solid agent and the like. Can be mentioned. Among them, emulsions such as creams, emulsions and gel emulsions, lotions, beauty essences and cosmetics are preferable as embodiments of the present invention because they are easy to apply over a wide range.

The composition for external use of the present invention contains pharmaceuticals, non-pharmaceutical products or cosmetics as necessary within a quantitative and qualitative range that does not impair the quality such as storage stability and viscosity and does not impair the effects of the present invention. Various components commonly used in the field, such as water, oily components (eg hydrocarbons, vegetable oils, ester oils, higher alcohols, silicone oils, fatty acids, etc.), polyhydric alcohols, thickeners, lower alcohols, surfactants. Agents, preservatives, pH adjusters, stabilizers, irritation reducing agents, preservatives, coloring agents, dispersants, fragrances and the like can be blended. It should be noted that these components can be blended alone or in any combination of two or more. Further, the blending amount of these components is not particularly limited as long as the effect of the present invention is obtained, but preferably, it is appropriately selected up to a pharmaceutically acceptable upper limit blending amount.

The external composition of the present invention may further contain an active ingredient in order to give the composition a desired effect. In the present invention, the active ingredient is an ingredient having a useful effect on the skin such as a pharmacologically active ingredient and a physiologically active ingredient, and is not particularly limited. For example, a non-steroidal anti-inflammatory agent, vitamins, whitening agent, anti-inflammatory agent. Wrinkles, anti-inflammatory analgesics, antifungal agents, steroids, hair restorers, slimming agents, local anesthetics, antipruritic agents, antibacterial agents, antiviral agents, keratin softeners, moisturizers, astringents, antioxidants, hair growth Examples thereof include an inhibitor, an ultraviolet absorber, and an ultraviolet scattering agent. These components can be used alone or in combination of two or more. Further, the blending amount of these components is not particularly limited as long as the effect of the present invention is obtained, but preferably, it is appropriately selected up to a pharmaceutically acceptable upper limit blending amount.

The external composition of the present invention is usually used by being filled in a container. Such a container can be stored in a container of an appropriately selected shape and material according to the purpose and use of use, and can be used without particular limitation as long as it is normally used in the technical field. can.
As the material of the container (main body, cap, discharge member, inner plug, seal member, etc.), the innermost layer considers the storage stability of the external composition, chemical resistance, strength, flexibility, weather resistance, etc. of the container. For example, polyethylene, polypropylene, polyethylene terephthalate, polystyrene, aluminum, polyvinyl chloride, ABS resin, ethylene-vinyl alcohol resin, acrylonitrile / styrene resin, epoxy resin, polyamide / imide resin, glass and the like may be selected as appropriate. Can be mentioned. Preferably, as the container material, a container having an innermost layer of polyethylene, polypropylene, polyethylene terephthalate, aluminum, epoxy resin, polyamide-imide resin and glass can be mentioned. Further, a laminate using these container resins may be used.

The external composition of the present invention can be used as a composition for treating, preventing or ameliorating various symptoms and diseases. The amount and usage of the external composition of the present invention applied to the outer skin is not particularly limited, and the composition can be usually used by applying an appropriate amount to the outer skin such as skin several times a day.

The external composition of the present invention is particularly preferably used for a symptom or disease in which diphenhydramine or a salt thereof and a mucopolysaccharide have a therapeutic, preventive or ameliorating effect. Examples of such symptoms and diseases include itching symptoms; symptoms caused by dry skin; diseases showing itching symptoms and symptoms caused by dry skin; and the like.
Specific examples of symptoms caused by dry skin include debris on the surface of the skin, dusting, fluff, dryness, cracks, cracks, keratinization of elbows, knees, heels, ankles, fine wrinkles on the face, and skin. There are decreased flexibility, rough fingers, itching, dry skin, sensitive skin, skin irritation, erythema, atopy skin, rough skin, etc.
Specific examples of diseases showing itching and dry skin include dry skin, senile dry skin, pediatric dry skin, scaly vulgaris (shark skin), atopic dermatitis, and allergic skin. Examples include inflammation, sebum-reducing eczema, sensitive skin, seasonal dry skin, aqueous pruritus, housewife eczema, dermatitis, rash, urticaria, insect bites, eczema, sores, rashes, and rashes.
The external composition of the present invention is particularly effective for diseases associated with itching and showing symptoms caused by dry skin (for example, xerosis, senile xerosis, pediatric dry skin, etc.).

The external composition of the present invention is particularly preferably used for a symptom or disease in which ascorbic acid or a salt thereof and a mucopolysaccharide have a therapeutic, preventive or ameliorating effect. Examples of such symptoms and diseases include inflammatory symptoms; symptoms caused by skin inflammation; diseases showing rough skin symptoms and symptoms caused by skin inflammation; acne and the like. Specific examples of symptoms caused by skin inflammation include cracks, cracks, rough fingers, itching, dry skin (dry skin), sensitive skin, skin irritation, erythema, atopy skin, rough skin, sunburn stains, freckles, etc. There is.
The external composition of the present invention is particularly effective for diseases showing symptoms caused by skin inflammation (for example, acne, sunburn spots, freckles).

Hereinafter, the present invention will be described in detail based on examples, but the present invention is not limited to these examples. In each of the following examples,% means mass (W / W)% unless otherwise specified.

Test Example 1 Diphenhydramine was added to the thermal stability and photostability test oil phase of a cream containing diphenhydramine (a mixture of isopropyl palmitate, liquid paraffin, cetomacrogol, glycerin monostearate, cetanol, and white petrolatum), and 70 Heated to ° C. Similarly, a heparinoid was added to the aqueous phase (purified water, concentrated glycerin, methyl paraoxybenzoate, carboxyvinyl polymer, and sodium edetate mixed and stirred), and the mixture was heated to 70 ° C. The two phases (oil phase and aqueous phase) were stirred and emulsified at high temperature and cooled to room temperature to obtain the cream of Example 1 having the composition shown in Table 1.
The cream of Comparative Example 1 was produced in the same manner as the cream of Example 1 except that a heparinoid was not added.

About 40 g of each of the external compositions of Example 1 and Comparative Example 1 was placed in a transparent screw cap bottle of a thermal stability test of 50 ml, stored at 60 ° C. for 3 days, and the color change was visually observed. The results are shown in Table 1.
Optical stability test
Approximately 40 g of each of the compositions of Example 1 and Comparative Example 1 was placed in a 50 ml transparent screw cap bottle, irradiated with light at 20 to 25 ° C. (total illuminance of 1.2 million lux · hr), and visually colored. The change was observed. The results are shown in Table 1.

As shown in Table 1, in both the thermal and photostability tests, Example 1 containing a heparinoid was compared with Comparative Example 1 not containing a heparinoid over time of the external composition. It was confirmed that discoloration was suppressed.

Test Example 2 The thermal stability and photostability test oil phase of the diphenhydramine-containing emulsion (a mixture of isopropyl palmitate, phytosterol, polyoxyethylene hydrogenated castor oil, and white petrolatum) was added with diphenhydramine and heated to 70 ° C. Similarly, a heparinoid was added to the aqueous phase (purified water, concentrated glycerin, methyl paraoxybenzoate, sodium citrate, and citric acid mixed and dissolved), and the mixture was heated to 70 ° C. The two phases (oil phase and aqueous phase) were stirred and emulsified at high temperature, xanthan gum was added and stirred, and the mixture was cooled to room temperature to obtain the emulsion of Example 2 having the composition shown in Table 2.
The emulsion of Comparative Example 2 was produced in the same manner as the emulsion of Example 2 except that a heparinoid was not added.

About 40 g of each of the external compositions of Example 1 and Comparative Example 1 was placed in a transparent screw cap bottle having a thermal stability test of 50 ml, stored at 60 ° C. for 1 day, and the color change was visually observed. The results are shown in Table 2.

As shown in Table 2, in the thermal stability test, Example 2 containing a heparin-like substance suppressed discoloration of the external composition over time as compared with Comparative Example 2 containing no heparin-like substance. It was confirmed that he was there. Similar to the thermal stability, the photostability of the external composition of Test Example 2 has the same tendency as that of Test Example 1.

Test Example 3 Thermal stability and photostability test of ascorbic acid-containing lotion (beauty liquid) Purified water, concentrated glycerin, 1.3-butylene glycol, propylene glycol, methyl paraoxybenzoate, sodium edetate, ascorbic acid, heparin A similar substance was mixed and dissolved at 40 ° C. and cooled to room temperature to obtain a lotion (beauty liquid) of Example 3 having the composition shown in Table 1.
The lotion (beauty essence) of Comparative Example 3 was produced in the same manner as the lotion (beauty essence) of Example 3 except that a heparin-like substance was not added.

Thermal stability test About 40 g of each of the external compositions of Example 3 and Comparative Example 3 was placed in a transparent screw cap bottle of 50 ml, stored at 60 ° C. for 3 days, and the color change was visually observed. The results are shown in Table 3.
Optical stability test
Approximately 40 g of each of the compositions of Example 1 and Comparative Example 1 was placed in a 50 ml transparent screw cap bottle, irradiated with light at 20 to 25 ° C. (total illuminance of 1.2 million lux · hr), and visually colored. The change was observed. The results are shown in Table 3.

As shown in Table 3, in both the thermal and photostability tests, Example 3 containing a heparinoid was compared with Comparative Example 3 not containing a heparinoid over time of the external composition. It was confirmed that discoloration was suppressed.

Examples of the pharmaceutical product are given below, but the present invention is not limited to these examples. As the container material for accommodating the formulation examples, a container whose innermost layer is polyethylene, polypropylene, polyethylene terephthalate, aluminum, epoxy resin, polyamide-imide resin and glass can be used. The unit of each compounding component shall mean weight (W / W)%.

Claims (16)

An external composition containing ascorbic acid or a salt thereof and a heparinoid (but not heparin or a salt thereof, chondroitin sulfate or a salt thereof, and dermatan sulfate or a salt thereof).
(1) An external composition containing a polymer of 2-methacryloyloxyethyl phosphorylcholine ,
(2) 0.1 part by weight of sodium ascorbate, 5 parts by weight of glycerin, 0.1 part by weight of sulfated trehalose sodium, 0.1 part by weight of heparin-like substance, 5 parts by weight of ethanol, 5 parts by weight of 1,3-butanediol. , A composition containing 0.1 parts by weight of methylparaben, and 84.6 parts by weight of water, and
(3) A composition containing polyacrylic acid and / or polyacrylic acid salt, one or more anti-inflammatory agents selected from glycyrrhetinic acid, glycyrrhizinic acid, and alkyl esters thereof, and water, in the form of a sheet. Except for the composition to make up the pack ). The external composition according to claim 1, which is a liquid preparation. The external composition according to claim 1 or 2, which contains a heparinoid in a weight ratio of 0.003 to 10 parts by weight with respect to 1 part by weight of ascorbic acid or a salt thereof. The external composition according to any one of claims 1 to 3, wherein the concentration of ascorbic acid or a salt thereof is 0.1 to 30% by weight based on the entire external composition. The external composition according to any one of claims 1 to 4, wherein the concentration of the heparinoid is 0.005 to 10% by weight based on the entire external composition. The external composition according to any one of claims 1 to 5, wherein the innermost layer is filled in a container containing polyethylene, polypropylene, polyethylene terephthalate, aluminum, epoxy resin, polyamide-imide resin, or glass. The external composition according to any one of claims 1 to 6, further comprising silicone oil, fatty acid, white petrolatum, propylene glycol, and / or concentrated glycerin. The external composition according to any one of claims 1 to 7, which is a composition for external use on the skin. The external composition according to any one of claims 1 to 8, wherein the discoloration is suppressed. The external composition according to any one of claims 1 to 9, wherein the discoloration is due to heat and / or light. The external composition according to any one of claims 1 to 10, which does not contain carotenoids. In an external composition containing ascorbic acid or a salt thereof, it contains ascorbic acid or a salt thereof in which a heparinoid (but not heparin or a salt thereof, chondroitin sulfate or a salt thereof, and dermatan sulfate or a salt thereof) coexists. A method for suppressing discoloration of an external composition. A discoloration inhibitor for an external composition containing ascorbic acid or a salt thereof, which comprises a heparin-like substance (provided that heparin or a salt thereof, chondroitin sulfate or a salt thereof, and dermatan sulfate or a salt thereof are not used) as an active ingredient. The external composition according to any one of claims 1 to 11, wherein the external composition further comprises water. 12. The method of claim 12, wherein the external composition further comprises water. The agent according to claim 13, wherein the external composition further comprises water.