External composition

Abstract

To provide a formulation technique for a topical composition comprising diphenhydramine and / or a salt thereof, glycyrrhizic acid, a derivative thereof, and / or salts of them, allantoin and / or a derivative thereof, and a heparinoid, whereby the discoloration of it due to storage can be inhibited and excellent formulation stability is achieved.SOLUTION: A topical composition comprises diphenhydramine and / or a salt thereof, glycyrrhizic acid, a derivative thereof, and / or salts of them, allantoin and / or a derivative thereof, and a heparinoid in combination with a sorbitan fatty acid ester and / or a polyoxyethylene alkyl ether. The topical composition can resist being discolored during its storage and demonstrates excellent formulation stability.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an external composition containing diphenhydramine and / or its salt, glycyrrhizic acid, its derivative, and / or their salt, allantoin and / or its derivative, and a heparin-like substance, which can suppress discoloration caused by storage.

Background Art

[0002] It is known that diphenhydramine and its salt have an antihistamine action, glycyrrhizic acid and its salt have an anti-inflammatory action, allantoin has a tissue repair and activation action, an anti-inflammatory action, etc., and a heparin-like substance has a moisturizing action, a blood circulation promoting action, etc.

[0003] In recent years, multifunctionality has been required for external compositions, and formulation prescriptions using the above-mentioned components in combination have been reported. For example, Patent Document 1 describes that a topical skin preparation containing (A) a heparin-like substance, (B) at least one selected from the group consisting of tocopherol, tocopherol acetate, tocopherol nicotinate, tocopherol linolenate, tocopherol succinate, panthenol, and vitamin A compounds, (C) at least one anti-inflammatory agent selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, stearyl glycyrrhetinate, allantoin, and their salts, and (D) at least one antipruritic agent selected from the group consisting of diphenhydramine and diphenhydramine hydrochloride can fundamentally treat dry skin diseases accompanied by itching.

[0004] However, in order to put an external composition into practical use, not only functionality but also sufficient consideration must be given to formulation stability. However, in the prior art, sufficient studies have not been made on the formulation stability of external compositions using the above-mentioned components in combination.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] The present inventor has conducted studies to commercialize an external composition containing diphenhydramine and / or its salt, glycyrrhizic acid, its derivatives, and / or their salts, allantoin, and a heparin-like substance. As a result, it has been found that in this external composition, discoloration (yellowing) occurs during storage, and it is impossible to maintain good appearance properties, and there is a new problem of poor formulation stability.

[0007] Therefore, an object of the present invention is to provide a formulation technology that can suppress discoloration caused by storage and has excellent formulation stability in an external composition containing diphenhydramine and / or its salt, glycyrrhizic acid, its derivatives, and / or their salts, allantoin and / or its derivatives, and a heparin-like substance.

Means for Solving the Problems

[0008] The present inventor has conducted intensive studies to solve the above problems and found that an external composition formulated by combining sorbitan fatty acid ester and / or polyoxyethylene alkyl ether together with diphenhydramine and / or its salt, glycyrrhizic acid, its derivatives and / or their salts, allantoin and / or its derivatives, and a heparin-like substance can suppress discoloration (yellowing) caused by storage and can have excellent formulation stability. The present invention has been completed by further studies based on such findings.

[0009] That is, the present invention provides an invention in the following aspects. Item 1. An external composition containing (A) diphenhydramine and / or a salt thereof, (B) at least one selected from the group consisting of glycyrrhizic acid, derivatives thereof, and salts thereof, (C) allantoin and / or a derivative thereof, (D) a heparin analogue, and (E) a sorbitan fatty acid ester and / or a polyoxyethylene alkyl ether. Item 2. The external composition according to Item 1, further containing (F) triethanolamine.

Advantages of the Invention

[0010] According to the external composition of the present invention, although it contains diphenhydramine and / or a salt thereof, glycyrrhizic acid and / or a salt thereof, allantoin, and a heparin analogue, it can suppress discoloration due to storage and can have excellent formulation stability.

Modes for Carrying Out the Invention

[0011] 1. External composition The external composition of the present invention is characterized by containing (A) diphenhydramine and / or a salt thereof, (B) at least one selected from the group consisting of glycyrrhizic acid, derivatives thereof, and salts thereof, (C) allantoin and / or a derivative thereof, (D) a heparin analogue, and (E) a sorbitan fatty acid ester and / or a polyoxyethylene alkyl ether. Hereinafter, the external composition of the present invention will be described in detail.

[0012] [(A) Diphenhydramine and / or a salt thereof] The external composition of the present invention contains diphenhydramine and / or a salt thereof (sometimes referred to as component (A)). Diphenhydramine is a known drug known to have an antihistamine effect.

[0013] The salts of diphenhydramine are not particularly limited as long as they are pharmaceutically acceptable. Specifically, acid addition salts such as hydrochloride, citrate, succinate, tartrate, fumarate, maleate, salicylate, diphenyldisulfonate, tannate, lauryl sulfate, and sulfate can be mentioned. These salts may be used alone or in combination of two or more.

[0014] In the external composition of the present invention, as the component (A), one kind may be selected from diphenhydramine and its salts, or two or more kinds may be used in combination.

[0015] Among these component (A), preferably diphenhydramine and diphenhydramine hydrochloride can be mentioned.

[0016] The content of the component (A) in the external composition of the present invention may be appropriately set according to the degree of medicinal effect to be provided in the external composition, etc. For example, the total amount of the component (A) is 0.01 to 5% by weight, preferably 0.05 to 3% by weight, more preferably 0.1 to 2% by weight, and still more preferably 0.2 to 0.8% by weight.

[0017] [(B) Glycyrrhizic acid, its derivatives and / or its salts] The external composition of the present invention contains at least one selected from the group consisting of glycyrrhizic acid, its derivatives and their salts (sometimes referred to as component (B)). Glycyrrhizic acid is a known drug having anti-inflammatory action, anti-allergic action, etc.

[0018] The derivatives of glycyrrhizic acid are not particularly limited as long as they are pharmaceutically acceptable. Specifically, methyl glycyrrhizinate, stearyl glycyrrhizinate, etc. can be mentioned.

[0019] The salts of glycyrrhizic acid and / or its derivatives are not particularly limited as long as they are pharmaceutically acceptable. Specifically, examples include alkali metal salts such as sodium salts and potassium salts, and ammonium salts.

[0020] In the external composition of the present invention, as the component (B), one kind may be selected from glycyrrhizic acid, derivatives of glycyrrhizic acid, and salts thereof, or two or more kinds may be used in combination.

[0021] Among these component (B), preferably glycyrrhizic acid and its salts, more preferably salts of glycyrrhizic acid, and even more preferably dipotassium glycyrrhizinate can be mentioned.

[0022] The content of the component (B) in the external composition of the present invention may be appropriately set according to the degree of medicinal efficacy to be provided in the external composition, etc. For example, the total amount of the component (B) is 0.01 to 5% by weight, preferably 0.05 to 2% by weight, and even more preferably 0.1 to 1% by weight.

[0023] In the external composition of the present invention, the ratio of the component (A) to the component (B) is determined according to the respective contents of the component (A) and the component (B). For example, per 1 part by weight of the total amount of the component (A), the component (B) is 0.01 to 100 parts by weight in total, preferably 0.1 to 10 parts by weight, and more preferably 0.5 to 5 parts by weight.

[0024] [(C) Allantoin and / or its derivatives] The external composition of the present invention contains allantoin and / or its derivatives (which may also be referred to as component (C)). Allantoin is a compound also known as 5-ureidohydantoin and is a known drug having functions such as tissue repair activation, anti-inflammatory action, and antipruritic action.

[0025] Derivatives of allantoin are not particularly limited as long as they are pharmaceutically acceptable. Specifically, examples include allantoin chlorohydroxyaluminum, allantoin hydroxyaluminum, allantoin dihydroxyaluminum, allantoin chlorohydroxyaluminum, and the like.

[0026] In the external composition of the present invention, as the component (C), one kind may be selected from allantoin and its derivatives and used, or two or more kinds may be used in combination.

[0027] Among these components (C), allantoin is preferably mentioned.

[0028] The content of the component (C) in the external composition of the present invention may be appropriately set according to the degree of medicinal effect to be provided in the external composition, etc. For example, the total amount of the component (C) is 0.01 to 5% by weight, preferably 0.1 to 3% by weight, more preferably 0.2 to 1% by weight.

[0029] In the external composition of the present invention, the ratio of the component (A) to the component (C) is determined according to the respective contents of the component (A) and the component (C). For example, per 1 part by weight of the total amount of the component (A), the component (C) is 0.001 to 20 parts by weight in total, preferably 0.005 to 1 part by weight, more preferably 0.05 to 5 parts by weight.

[0030] [(D) Heparin - like substance] The external composition of the present invention contains a heparin - like substance (sometimes referred to as component (D)). The heparin - like substance is a polysulfated mucopolysaccharide such as chondroitin polysulfate, and is a known drug known to have a moisturizing effect, a blood circulation promoting effect, and the like.

[0031] The origin of the heparin - like substance used in the present invention is not particularly limited. For example, those obtained by polysulfating mucopolysaccharides, those extracted from the tissues of edible animals (e.g., lungs including bovine tracheal cartilage), etc. can be mentioned. In the external emulsion composition of the present invention, as the heparin - like substance, the heparin - like substance listed in the Japanese Pharmaceutical Excipients Standard is preferably used.

[0032] The content of the component (D) in the external composition of the present invention can be appropriately set according to the degree of medicinal effect to be provided in the external composition, etc. For example, the total amount of the component (D) is 0.01 to 10% by weight, preferably 0.05 to 0.5% by weight, more preferably 0.1 to 0.4% by weight.

[0033] In the external composition of the present invention, the ratio of the component (A) to the component (D) is determined according to the respective contents of the component (A) and the component (D). For example, per 1 part by weight of the total amount of the component (A), the component (D) is 0.001 to 20 parts by weight in total, preferably 0.005 to 1 part by weight, more preferably 0.06 to 6 parts by weight.

[0034] [(E) Sorbitan fatty acid ester and / or polyoxyethylene alkyl ether] The external composition of the present invention contains sorbitan fatty acid ester and / or polyoxyethylene alkyl ether (sometimes referred to as component (E)). In the prior art, in the pharmaceutical composition containing the components (A) to (D), discoloration occurs during storage. However, in the pharmaceutical composition of the present invention, by containing the component (E) together with the components (A) to (D), it is possible to suppress the discoloration caused by storage and have excellent formulation stability.

[0035] Sorbitan fatty acid esters are esters of sorbitan and fatty acids and are well-known nonionic surfactants. The number of fatty acids bonded per molecule of sorbitan fatty acid ester is not particularly limited, and examples thereof include 1 to 4, preferably 1 to 3, more preferably 1 or 2, and still more preferably 1. The number of carbon atoms of the fatty acid constituting the sorbitan fatty acid ester is not particularly limited, and examples thereof include 10 to 22, preferably 14 to 22, and more preferably 16 to 20. Specific examples of the sorbitan fatty acid ester include sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate, sorbitan sesquistearate, sorbitan coconut oil fatty acid, sorbitan monopalmitate, sorbitan tristearate, sorbitan trioleate, and the like. Among these sorbitan fatty acid esters, from the viewpoint of more effectively suppressing discoloration due to storage, sorbitan monostearate, sorbitan monooleate, and sorbitan monopalmitate are preferable, and sorbitan monostearate is more preferable.

[0036] Polyoxyethylene alkyl ether is a compound in which a polyoxyethylene chain is ether-bonded to an alkyl group or an alkenyl group, and is a known nonionic surfactant. The average number of moles of ethylene oxide (EO) added to form the polyoxyethylene alkyl ether is not particularly limited, but examples include 5 to 40 moles, preferably 10 to 30 moles, and more preferably 15 to 25 moles. The number of carbon atoms in the alkyl group or alkenyl group that constitutes the polyoxyethylene alkyl ether is not particularly limited, but examples include 10 to 24, preferably 14 to 24, and more preferably 15 to 24. Specific examples of the polyoxyethylene alkyl ether include polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, polyoxyethylene behenyl ether, and the like. Among these polyoxyethylene alkyl ethers, from the viewpoint of more effectively suppressing discoloration due to storage, polyoxyethylene behenyl ether, polyoxyethylene cetyl ether, and polyoxyethylene stearyl ether are preferred, and polyoxyethylene behenyl ether is more preferred.

[0037] In the external composition of the present invention, as the component (E), one kind may be selected from sorbitan fatty acid esters and polyoxyethylene alkyl ethers and used, or two or more kinds may be used in combination.

[0038] From the viewpoint of more effectively suppressing discoloration due to storage, it is preferable to use a combination of a sorbitan fatty acid ester and a polyoxyethylene alkyl ether as the component (E). When using a combination of a sorbitan fatty acid ester and a polyoxyethylene alkyl ether, the ratio thereof is not particularly limited, but for example, the polyoxyethylene alkyl ether is 0.01 to 150 parts by weight, preferably 0.05 to 15 parts by weight, and more preferably 0.1 to 20 parts by weight per 1 part by weight of the sorbitan fatty acid ester.

[0039] As the content of the component (E) in the external composition of the present invention, for example, the total amount of the component (E) is 0.1 to 25% by weight, preferably 0.5 to 12% by weight, more preferably 1 to 12% by weight. More specifically, in the case of sorbitan fatty acid ester, the content of sorbitan fatty acid ester in the external composition of the present invention is, for example, 0.1 to 10% by weight, preferably 0.5 to 5% by weight, more preferably 1 to 5% by weight. In the case of polyoxyethylene alkyl ether, the content of polyoxyethylene alkyl ether in the external composition of the present invention is, for example, 0.1 to 15% by weight, 0.5 to 7% by weight, more preferably 1.5 to 7% by weight.

[0040] In the external composition of the present invention, the ratio of the component (A) to the component (E) is determined according to the respective contents of the component (A) and the component (E). For example, per 1 part by weight of the total amount of the component (A), the component (E) is 0.01 to 160 parts by weight in total, preferably 0.05 to 130 parts by weight, more preferably 0.2 to 80 parts by weight. More specifically, in the case of sorbitan fatty acid ester, per 1 part by weight of the total amount of the component (A), sorbitan fatty acid ester is 0.01 to 60 parts by weight, preferably 0.05 to 40 parts by weight, more preferably 0.2 to 30 parts by weight. In the case of polyoxyethylene alkyl ether, per 1 part by weight of the total amount of the component (A), polyoxyethylene alkyl ether is 0.01 to 100 parts by weight, preferably 0.05 to 70 parts by weight, more preferably 0.4 to 50 parts by weight.

[0041] [(F) Triethanolamine] The external composition of the present invention may contain triethanolamine (sometimes referred to as the component (F)) as needed. In particular, when the dosage form of the external composition of the present invention is a cream, if triethanol is contained in addition to the components (A) to (E), both the hardness of the cream and the elongation on the skin during application can be improved, and an excellent usability can be provided.

[0042] When the component (F) is contained in the external composition of the present invention, the content thereof is not particularly limited. For example, it may be 0.001 to 10% by weight, preferably 0.01 to 4% by weight, more preferably 0.05 to 4% by weight, and still more preferably 0.2 to 1% by weight.

[0043] When the component (F) is contained in the external composition of the present invention, the ratio of the component (A) to the component (F) is determined according to the respective contents of the component (A) and the component (F). For example, per 1 part by weight of the total amount of the component (A), the component (F) is 0.001 to 20 parts by weight, preferably 0.005 to 10 parts by weight, more preferably 0.05 to 5 parts by weight, and still more preferably 0.4 to 5 parts by weight.

[0044] [Surfactant other than component (E)] The external composition of the present invention may contain a surfactant other than the component (E) as necessary. Examples of the surfactant other than the component (E) include nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants, etc. other than the component (E). These surfactants may be used alone or in combination of two or more. Among these surfactants, nonionic surfactants are preferably mentioned.

[0045] The nonionic surfactant (other than the component (E)) used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, polyoxyethylene sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene hydrogenated castor oil, etc. may be mentioned. These nonionic surfactants (other than the component (E)) may be used alone or in combination of two or more.

[0046] Among these nonionic surfactants, polyoxyethylene sorbitan fatty acid ester and glycerin fatty acid ester are preferably mentioned.

[0047] The average number of moles of ethylene oxide (EO) constituting the polyoxyethylene sorbitan fatty acid ester is not particularly limited, and examples thereof include 5 to 40 moles, preferably 10 to 30 moles, and more preferably 15 to 25 moles. The number of carbon atoms of the fatty acid constituting the polyoxyethylene sorbitan fatty acid ester is not particularly limited, and examples thereof include 10 to 22, preferably 14 to 22, and more preferably 16 to 20. Specific examples of the polyoxyethylene sorbitan fatty acid ester include polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monostearate, and the like. Among these polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan monostearate (polysorbate 60) in which the average number of moles of ethylene oxide (EO) is 20 is preferably mentioned.

[0048] The number of carbon atoms of the fatty acid constituting the glycerin fatty acid ester is, for example, 10 to 22, preferably 14 to 22, and more preferably 16 to 20. The number of fatty acids bonded per molecule of glycerin fatty acid is not particularly limited, and examples thereof include 1 to 3, preferably 1 or 2, and more preferably 1. Specific examples of the glycerin fatty acid ester include glyceryl monostearate, glyceryl monoisostearate, glyceryl monooleate, glyceryl dimyristate, glyceryl distearate, and the like. Among these glycerin fatty acid esters, glyceryl monostearate is preferably mentioned.

[0049] When the external composition of the present invention contains a surfactant other than the component (E), the content thereof is not particularly limited, and examples thereof include 0.01 to 20% by weight, preferably 0.05 to 10% by weight, and more preferably 0.1 to 5% by weight based on the total amount of the surfactant other than the component (E).

[0050] [Polyhydric alcohol] The external composition of the present invention may contain a polyhydric alcohol, if necessary. The polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include 1,3-butylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, glycerin, and the like. Among these polyhydric alcohols, 1,3-butylene glycol and glycerin are preferable, and 1,3-butylene glycol is more preferable. These polyhydric alcohols may be used alone or in combination of two or more.

[0051] When the external composition of the present invention contains a polyhydric alcohol, the content thereof is not particularly limited. For example, the total amount of the polyhydric alcohol is 1 to 30% by weight, preferably 2 to 25% by weight, and more preferably 4 to 20% by weight.

[0052] [Oily base] The external composition of the present invention may contain an oily base, if necessary, for the preparation into a desired dosage form or the like. The oily base is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include higher alcohols, hydrocarbon oils, fatty acid alkyl esters, fatty acids, vegetable oils, animal oils, silicone oils, and the like. These oily bases may be used alone or in combination of two or more.

[0053] Among these oily bases, higher alcohols, hydrocarbon oils, and fatty acid alkyl esters are preferable.

[0054] The higher alcohol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include monohydric alcohols having 12 to 34 carbon atoms. Specifically, lauryl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, oleyl alcohol, behenyl alcohol, myristyl alcohol, gedil alcohol, and the like can be mentioned. Among these higher alcohols, cetyl alcohol and stearyl alcohol are preferable.

[0055] The hydrocarbon oil is not particularly limited as long as it is pharmaceutically acceptable. Examples thereof include liquid paraffin, α-olefin oligomer, petrolatum, microcrystalline wax, hydrogenated polyisobutene, and the like. Among these hydrocarbon oils, liquid paraffin and petrolatum are preferably mentioned.

[0056] Examples of the fatty acid alkyl ester include esters of fatty acids having 4 to 30 carbon atoms and alcohols having 1 to 34 carbon atoms. Specifically, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, cetyl palmitate, diethyl sebacate, and the like can be mentioned. Among these fatty acid alkyl esters, isopropyl myristate is preferably mentioned.

[0057] When the external composition of the present invention contains an oily base, its content may be appropriately set according to the dosage form, feeling in use, etc. For example, it is 0.1 to 60% by weight, preferably 1 to 40% by weight, more preferably 10 to 30% by weight based on the total amount of the oily base.

[0058] [Water] The external composition for the skin of the present invention can contain water as a base material. When the external composition of the present invention contains an oily base, its content may be appropriately set according to the dosage form, feeling in use, etc. For example, it is 10 to 90% by weight, preferably 20 to 85% by weight, more preferably 40 to 85% by weight.

[0059] [Other components] In addition to the components described above, the external composition of the present invention may contain other commonly used additives as necessary. Examples of such additives include monohydric lower alcohols, thickeners, solvents, pH adjusters, buffers, solubilizers, antiseptics, preservatives, antioxidants, stabilizers, fragrances, colorants, and the like. When these additives are contained in the external composition of the present invention, their content may be appropriately set according to the type of additive used, etc.

[0060] In addition to the aforementioned components, the external composition of the present invention may contain a pharmacological component. Examples of such pharmacological components include steroid agents, antihistamines (other than component (A)), local anesthetics, anti-inflammatory agents (other than component (B) and component (C)), moisturizing agents (other than component (D)), bactericides, antibacterial agents, antipruritics, skin protectants, blood circulation promoting components (other than component (D)), vitamins, mucopolysaccharides, and the like. These pharmacological components may be used alone or in combination of two or more. Further, in the external composition of the present invention, when these pharmacological components are contained, the concentration thereof may be appropriately set according to the type of pharmacological component used, the expected effect, and the like.

[0061] [pH] The pH of the external composition of the present invention is not particularly limited, and examples thereof include 2 to 9, preferably 3 to 8, more preferably 4 to 7.5, and still more preferably 4 to 5.5.

[0062] [Dosage form · Formulation form] The dosage form of the external composition of the present invention is not particularly limited as long as it can be applied transdermally, and it may be any of liquid, semi-solid (cream-like, gel-like, ointment-like, paste-like), solid, etc., but preferably liquid or semi-solid. Further, the external composition of the present invention may be an emulsified preparation such as an oil-in-water type emulsified preparation or a water-in-oil type emulsified preparation, or may be a non-emulsified preparation such as a solubilized type preparation or an aqueous ointment. As the external composition of the present invention, a cream-like oil-in-water type emulsified preparation is preferably mentioned.

[0063] Specific examples of the formulation form of the external composition of the present invention include skin-external pharmaceuticals such as creams, lotions, gels, emulsions, liquids, poultices, patches, liniments, aerosols, aqueous ointments, packs, etc.; cosmetics such as aqueous ointments, creams, emulsions, lotions, packs, gels, etc. Among these, skin-external pharmaceuticals are preferably mentioned.

[0064] Since the external composition of the present invention exhibits the medicinal effects based on the components (A) to (D), for example, it can be used to improve skin roughness and tightness after minor burns; keratosis of the elbows, knees, heels, and ankles; roughness of the fingers, cracks and red streaks on the hands and feet; dry skin, dry skin in children, heat rash, the clearing after bruising and sprains, muscle pain and joint pain, skin roughness, dry skin diseases, inflammatory skin diseases, hypertrophic scars, keloids, etc.

Example

[0065] Examples are shown below to more specifically explain the present invention, but the present invention is not limited thereto.

[0066] Test Example 1 External compositions (cream-like oil-in-water emulsified preparations) having the compositions shown in Tables 1 and 2 were prepared. Specifically, first, a surfactant (sorbitan monostearate, sorbitan monooleate, polyoxyethylene behenyl ether, polyoxyethylene cetyl ether, glyceryl monostearate, polysorbate 60, polyoxyethylene hydrogenated castor oil 60), and an oily base (stearyl alcohol, cetyl alcohol, white petrolatum, liquid paraffin, isopropyl myristate, diphenhydramine) were mixed in predetermined amounts and heated and dissolved at 80°C to prepare an oil-phase composition. Separately, dipotassium glycyrrhizinate, allantoin, heparin-like substance, carboxyvinyl polymer, 1,3-butylene glycol, citric acid, and water were mixed in predetermined amounts to prepare an aqueous-phase composition. Next, the aqueous-phase composition heated to 80°C was gradually added to the oil-phase composition heated to 80°C and mixed to perform an emulsification operation, and an external composition (cream-like oil-in-water emulsified preparation) was obtained. All of the external compositions immediately after production were white in color.

[0067] Each obtained external composition (10 g) was filled into a 13.5-ml glass bottle and stored under light-shielded conditions at 50°C for one month. The appearance of each external composition after one-month storage was visually observed, and the degree of yellowing was scored between 1 and 15 points, with "no yellowing observed at all and no problem for practical use" being 15 points and "significant yellowing observed and not suitable for practical use" being 1 point.

[0068] The results are shown in Tables 1 and 2. In the external compositions containing diphenhydramine, dipotassium glycyrrhizinate, and allantoin, no yellowing due to storage occurred when no heparin-like substance was included (Reference Examples 1 and 2). On the other hand, in the external compositions containing diphenhydramine, dipotassium glycyrrhizinate, allantoin, and a heparin-like substance, significant yellowing due to storage was observed when no sorbitan fatty acid ester or polyoxyethylene alkyl ether was included (Comparative Examples 1 to 3).

[0069] In contrast, in the external compositions containing diphenhydramine, dipotassium glycyrrhizinate, allantoin, a heparin-like substance, and sorbitan fatty acid ester and / or polyoxyethylene alkyl ether, yellowing due to storage was effectively suppressed (Examples 1 to 9). In particular, when both sorbitan fatty acid ester and polyoxyethylene alkyl ether were included, the effect of suppressing yellowing due to storage was further improved (Examples 1 and 6 to 9). Especially, when sorbitan monostearate and polyoxyethylene behenyl ether were used in combination, yellowing due to storage was remarkably suppressed (Examples 1 and 6). Also, in the external compositions in which the pH of each of the external compositions of Examples 1 to 9 was changed to 4.2 or 5.5, yellowing due to storage could be suppressed in the same manner as in Examples 1 to 9. Further, in the external composition in which sorbitan monooleate in the external composition of Example 9 was changed to sorbitan monopalmitate and polyoxyethylene cetyl ether was changed to polyoxyethylene stearyl ether (average number of moles of ethylene oxide added: 20), yellowing could be suppressed to the same extent as in Example 9.

[0070]

Table 1

[0071]

Table 2

[0072] Test Example 2 An external composition (cream-type oil-in-water emulsion preparation) having the composition shown in Table 3 was prepared by the same method as in Test Example 1. Ten subjects applied 2 g of each of the obtained external compositions to their arms and evaluated the hardness, elongation, and overall application feeling at the time of application. The evaluation of hardness was performed on a 5-point scale of "hard", "somewhat hard", "just right", "somewhat soft", and "soft", and the value obtained by rounding off the first decimal place of the percentage (%) of the total number of subjects who evaluated it as "just right" was calculated as the hardness score. The evaluation of elongation was performed on a 5-point scale of "strong", "somewhat strong", "just right", "somewhat weak", and "weak", and the value obtained by rounding off the first decimal place of the percentage (%) of the total number of subjects who evaluated it as "just right" was calculated as the elongation score. The evaluation of the overall application feeling was performed on a 4-point scale of "good", "somewhat good", "somewhat poor", and "poor", and the value obtained by rounding off the first decimal place of the percentage (%) of the total number of subjects who evaluated it as "good" was calculated as the overall application feeling score.

[0073] The results are shown in Table 3. As a result, in an external composition containing diphenhydramine, dipotassium glycyrrhizinate, allantoin, a heparin analogue, a sorbitan fatty acid ester and / or a polyoxyethylene alkyl ether, when further containing triethanolamine, it was found that the balance between the hardness and elongation felt at the time of application was excellent and an extremely excellent application feeling was obtained (Examples 10 and 11). Also, even when the pH of each external composition of Examples 10 and 11 was changed to 4.2 or 5.5, an extremely excellent application feeling was obtained in the same manner as in Examples 10 and 11.

[0074]

Table 3

[0075] Formulation Example When the external composition (oil-in-water type emulsion preparation in cream form) having the composition shown in Table 4 was evaluated for the degree of yellowing and the feeling of application by the methods of Test Examples 1 and 2, the external compositions of all of Formulation Examples 1 to 8 were excellent in the effect of suppressing yellowing and the feeling of application.

[0076]

Table 4

Claims

Claim 1 containing at least one selected from the group consisting of (A) diphenhydramine and / or its salts, (B) at least one selected from the group consisting of glycyrrhizic acid and its salts, (C) at least one selected from the group consisting of allantoin, allantoin chlorhydroxyaluminum, allantoin hydroxyaluminum, and allantoin dihydroxyaluminum, (D) heparin-like substances, and (E) sorbitan fatty acid monoesters and / or polyoxyethylene alkyl ethers, wherein the fatty acid constituting the sorbitan fatty acid monoesters has 10 to 22 carbon atoms, and the average number of moles of ethylene oxide added to the polyoxyethylene alkyl ethers is 5 to 40 moles and the alkyl group or alkenyl group has 10 to 24 carbon atoms, an external composition. Claim 2 The external composition according to claim 1, further containing (F) triethanolamine.

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