Topical composition

Abstract

To provide a topical composition which contains a heparinoid and allantoin and in which a change in appearance properties due to storage under unsealed conditions can be suppressed.SOLUTION: Provided is a topical emulsion composition comprising: (A) a heparinoid; (B) allantoin; (C) at least one component selected from the group consisting of glycyrrhetinic acid and derivatives thereof, and salts of glycyrrhetinic acid and the derivatives; and (D) ceramide 2.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to an external composition containing a heparin analogue and allantoin, which can suppress changes in appearance properties due to storage under unsealed conditions.

Background Art

[0002] Heparin analogues are known to have functions such as a moisturizing effect and a blood circulation promoting effect, and are used as components of external compositions. Allantoin has a tissue repair activating effect, an anti-inflammatory effect, an antipruritic effect, etc., and is used as a component of external compositions.

[0003] In recent years, there has been a strong demand for improving the functionality of external compositions. Focusing on the functionality of heparin analogues and allantoin, external compositions in which these components are used in combination to improve functionality have also been proposed. For example, Patent Document 1 reports that an external composition containing a heparin analogue, allantoin, and a nonionic surfactant exhibits an effect of suppressing melanin production due to their synergistic effect, and can suppress, prevent, or improve pigment deposition on the skin. Further, Patent Document 2 reports that an external pharmaceutical composition containing a heparin analogue, allantoin, and panthenol can promote normal differentiation of stratum corneum cells, increase the area of stratum corneum cells constituting the stratum corneum, and normalize the structure and function of the stratum corneum.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] In order to commercialize a topical composition, it is necessary to fully consider not only its effectiveness but also its formulation stability. The present inventors have conducted studies on topical compositions containing heparin-like substances and allantoin from various viewpoints, and have found that there are problems in terms of formulation stability. Specifically, it has been found that when a topical composition containing a heparin-like substance and allantoin is stored under non-sealed conditions, changes in appearance properties (separation of components and accompanying appearance changes) occur. Usually, topical compositions are stored in a sealed state, but since users may forget to close the lid of the container, it is desirable to be able to stably maintain the appearance properties even when stored under non-sealed conditions.

[0006] Therefore, an object of the present disclosure is to provide a topical composition containing a heparin-like substance and allantoin, which can suppress changes in appearance properties due to storage under non-sealed conditions.

Means for Solving the Problems

[0007] The present inventors have conducted intensive studies to solve the above problems, and as a result, have found that in a topical composition, by containing glycyrrhizic acids and ceramide 2 together with a heparin-like substance and allantoin, changes in appearance properties due to storage under non-sealed conditions can be suppressed. The present disclosure has been completed by further studies based on such findings.

[0008] That is, the present disclosure provides a topical composition in the following embodiments. Item 1. A topical composition containing (A) a heparin-like substance, (B) allantoin, (C) at least one selected from the group consisting of glycyrrhizic acid, its derivatives, and their salts, and (D) ceramide 2. Item 2. The topical composition according to claim 1, which is an emulsified preparation. Item 3. The topical composition according to claim 2, which is a cream preparation.

Effects of the Invention

[0009] According to the present disclosure, in an external composition containing a heparin analogue and allantoin, a formulation prescription is provided that can suppress changes in appearance properties due to storage under non-sealed conditions and has excellent formulation stability. Although the external composition may be stored under non-sealed conditions when the user inadvertently forgets to close the lid of the container, the external composition of the present disclosure can suppress changes in appearance properties even when stored under non-sealed conditions. Therefore, even in such an inappropriate storage state, changes in appearance properties can be suppressed.

Embodiments for Carrying Out the Invention

[0010] The external composition of the present disclosure is characterized by containing (A) a heparin analogue, (B) allantoin, (C) at least one selected from the group consisting of glycyrrhizic acid, its derivatives, and their salts, and (D) ceramide 2. Hereinafter, the external composition of the present disclosure will be described in detail. In the present disclosure, the description of the numerical range "X to Y" refers to the range of X or more and Y or less.

[0011] [(A) Heparin analogue] The external composition of the present disclosure contains a heparin analogue (sometimes also referred to as component (A)). A heparin analogue is a polysulfated mucopolysaccharide such as chondroitin polysulfate, and is a known component known to have a moisturizing effect and a blood circulation promoting effect. The origin of the heparin analogue used in the present disclosure is not particularly limited, and examples include those obtained by polysulfating mucopolysaccharides and those extracted from the tissues of edible animals (for example, lungs including bovine tracheal cartilage). In the external composition of the present disclosure, a heparin analogue included in the Japanese Pharmacopoeia for External Preparations is preferably used.

[0012] The content of component (A) in the external composition of the present disclosure may be appropriately set according to the use, formulation form, etc. of the external composition. For example, it may be 0.001 to 5% by weight, preferably 0.01 to 1% by weight, more preferably 0.01 to 0.3% by weight, and still more preferably 0.1 to 0.3% by weight.

[0013] [(B) Allantoin] The topical composition of the present disclosure contains allantoin (which may also be referred to as component (B)). Allantoin is a compound also known as 5-ureidohydantoin and is a known component known to have effects such as promoting tissue repair, anti-inflammatory effects, and antipruritic effects.

[0014] As the content of component (B) in the topical composition of the present disclosure, it may be appropriately set according to the use, formulation form, etc. of the topical composition. For example, 0.01 to 10% by weight, preferably 0.01 to 8% by weight, more preferably 0.01 to 1% by weight, and still more preferably 0.05 to 0.5% by weight can be mentioned.

[0015] [(C) Glycyrrhizic acids] The topical composition of the present disclosure contains at least one glycyrrhizic acid selected from the group consisting of glycyrrhizic acid, its derivatives, and their salts (which may also be referred to as component (C)). In the topical composition of the present disclosure, glycyrrhizic acids exhibit an effect of suppressing changes in the appearance properties due to storage under non-sealed conditions of the topical composition containing a heparin-like substance and allantoin by a synergistic effect with ceramide 2 described later.

[0016] Glycyrrhizic acid is a known drug known to have anti-inflammatory effects and anti-allergic effects, etc. 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. The salts of glycyrrhizic acid and its derivatives are not particularly limited as long as they are pharmaceutically acceptable. Specifically, alkali metal salts such as sodium salt and potassium salt; ammonium salts, etc. can be mentioned.

[0017] In the topical composition of the present disclosure, as component (C), one kind may be selected from glycyrrhizic acid, its derivatives, and their salts and used, or two or more kinds may be used in combination.

[0018] Among these component (C), from the viewpoint of more effectively suppressing the change in appearance properties due to storage under sealed conditions, preferably salts of glycyrrhizic acid, more preferably dipotassium glycyrrhizinate, can be mentioned.

[0019] In the external composition of the present disclosure, as the ratio of component (A) to component (C), for example, per 1 part by weight of component (A), component (C) is 0.01 to 100 parts by weight, preferably 0.05 to 50 parts by weight, more preferably 0.1 to 10 parts by weight, still more preferably 1 to 6 parts by weight.

[0020] The content of component (C) in the external composition of the present disclosure may be appropriately set according to the use, dosage form, etc. of the external composition. For example, it is 0.01 to 10% by weight, preferably 0.01 to 2.5% by weight, more preferably 0.1 to 2.5% by weight, still more preferably 0.5 to 2% by weight.

[0021] [(D) Ceramides 2] The external composition of the present disclosure contains ceramide 2 (which may also be referred to as component (D)). In the external composition of the present disclosure, ceramide 2 exerts an action of suppressing the change in appearance properties due to storage under non-sealed conditions of the external composition containing a heparin-like substance and allantoin by a synergistic effect with the above-mentioned glycyrrhizic acids. Ceramide 2 is N-stearoyl dihydrosphingosine and is one type of human ceramide.

[0022] In the external composition of the present disclosure, as the ratio of component (A) to component (D), for example, per 1 part by weight of component (A), component (D) is 0.005 to 50 parts by weight, preferably 0.02 to 25 parts by weight, more preferably 0.05 to 5 parts by weight, still more preferably 0.5 to 4 parts by weight, particularly preferably 1.3 to 4 parts by weight.

[0023] The content of the component (D) in the external composition of the present disclosure may be appropriately set according to the use, dosage form, etc. of the external composition. For example, it may be 0.001 to 10% by weight, preferably 0.001 to 5% by weight, more preferably 0.05 to 3% by weight, still more preferably 0.1 to 1.5% by weight, particularly preferably 0.3 to 1% by weight, and particularly more preferably 0.5 to 1% by weight.

[0024] [Water] The external composition of the present disclosure contains water in order to be prepared into a desired dosage form. The content of water in the external composition of the present disclosure may be appropriately set according to the dosage form, etc. For example, it may be 20 to 97% by weight, preferably 25 to 95% by weight, more preferably 30 to 90% by weight, still more preferably 35 to 80% by weight.

[0025] [Polyhydric alcohol] The external composition of the present disclosure may contain a polyhydric alcohol as necessary. The type of polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable. For example, dihydric alcohols such as ethylene glycol, 1,3-butylene glycol, propylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol, and polypropylene glycol; trihydric alcohols such as glycerin. Among these polyhydric alcohols, propylene glycol and 1,3-butylene glycol are preferably mentioned. These polyhydric alcohols may be used alone or in combination of two or more.

[0026] When the external composition of the present disclosure contains a polyhydric alcohol, its content is not particularly limited. For example, it may be 0.1 to 25% by weight, preferably 1 to 20% by weight, more preferably 2 to 15% by weight.

[0027] [Surfactant] The external composition of the present disclosure may contain a surfactant for preparing into a desired dosage form. The surfactant may be any of a nonionic surfactant, an anionic surfactant, a cationic surfactant, or an amphoteric surfactant, but preferably a nonionic surfactant.

[0028] The type of the nonionic surfactant is not particularly limited as long as it is pharmaceutically acceptable. For example, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, polyoxyethylene alkyl ether, polyethylene glycol fatty acid ester, lecithin derivative, etc. may be mentioned. Among these, examples of suitable nonionic surfactants include polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and glycerin fatty acid ester. These nonionic surfactants may be used alone or in combination of two or more.

[0029] When the external composition of the present disclosure contains a surfactant, its content may be appropriately set according to the dosage form, the type of the surfactant used, etc. For example, 0.1 to 20% by weight, preferably 0.5 to 10% by weight, more preferably 1 to 5% by weight may be mentioned.

[0030] [Thickener] The external composition of the present disclosure may contain a thickener as necessary for imparting viscosity or the like. The type of the thickener is not particularly limited as long as it is pharmaceutically acceptable. For example, carboxyvinyl polymer, xanthan gum, guar gum, locust bean gum, carrageenan, dextran, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium alginate, propylene glycol alginate ester, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, acrylic acid methacrylic acid alkyl copolymer, sodium polyacrylate bentonite, dextrin fatty acid ester, pectin and the like can be mentioned. Among these thickeners, carboxyvinyl polymer is preferably mentioned. These thickeners may be used alone or in combination of two or more.

[0031] When the external composition of the present disclosure contains a thickener, the content thereof is not particularly limited. For example, 0.05 to 5% by weight, preferably 0.1 to 3% by weight, more preferably 0.1 to 1% by weight can be mentioned.

[0032] [Chelating agent] The external composition of the present disclosure may contain a chelating agent as necessary. The type of the chelating agent is not particularly limited as long as it is pharmaceutically acceptable. For example, for example, edetic acid, citric acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, polyphosphoric acid, metaphosphoric acid, hexametaphosphoric acid, and pharmaceutically acceptable salts thereof and the like can be mentioned. Among these chelating agents, edetic acid and its salts are preferably mentioned, and sodium edetate is more preferably mentioned. These chelating agents may be used alone or in combination of two or more.

[0033] When a chelating agent is contained in the external composition of the present disclosure, its content is not particularly limited. For example, it may be 0.001 to 5% by weight, preferably 0.01 to 1% by weight, more preferably 0.05 to 0.5% by weight.

[0034] [Oil component] The external composition of the present disclosure may contain an oil component in order to be prepared into a desired dosage form. The type of the oil component is not particularly limited as long as it is pharmaceutically acceptable. For example, higher monohydric alcohols, fatty acid alkyl esters, hydrocarbon oils, silicone oils, vegetable oils, animal oils, cholesterol, etc. may be mentioned.

[0035] Among these oil components, as a preferred example, monohydric higher alcohols, fatty acid alkyl esters, hydrocarbon oils, and silicone oils may be mentioned. Examples of the monohydric higher alcohol include monohydric alcohols having 12 to 34 carbon atoms, specifically, myristyl alcohol, cetyl alcohol, oleyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol, hexadecyl alcohol, lanolin alcohol, etc. Examples of the fatty acid alkyl ester include esters of fatty acids having 6 to 30 carbon atoms and alcohols having 1 to 34 carbon atoms, specifically, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, cetyl palmitate, diethyl sebacate, ethyl oleate, etc. Specific examples of the hydrocarbon oil include paraffin, hydrogenated polyisobutene, liquid paraffin, gelled hydrocarbon (such as plastibase), ceresin, microcrystalline wax, white petrolatum, squalane, etc. Specific examples of the silicone oil include methylpolysiloxane, dimethylpolysiloxane, cyclic silicone, alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, acrylic silicone, phenyl-modified silicone, etc.

[0036] These oil components may be used alone or in combination of two or more.

[0037] When an oil component is contained in the external composition of the present disclosure, its content may be appropriately set according to the dosage form and the like. For example, it may be 1 to 60% by weight, preferably 5 to 50% by weight, more preferably 5 to 40% by weight, and still more preferably 10 to 30% by weight.

[0038] [Other components] In addition to the components described above, the external composition of the present disclosure may contain other commonly used additives as necessary. Examples of such additives include preservatives, monohydric lower alcohols, pH adjusters, buffers, solubilizers, antioxidants, stabilizers, fragrances, coloring agents, and the like. When these additives are contained in the external composition of the present disclosure, their content may be appropriately set according to the type of additive used and the like.

[0039] Further, in addition to the components described above, the external composition of the present disclosure may contain a pharmacological component. Examples of such pharmacological components include antihistamines, local anesthetics, moisturizers, bactericides, antibacterial agents, antipruritics, skin protectants, blood circulation promoting components, vitamins, and the like. These pharmacological components may be used alone or in combination of two or more. Also, when these pharmacological components are contained in the external composition of the present disclosure, their concentration may be appropriately set according to the type of pharmacological component used, the expected effect, and the like.

[0040] [Dosage form - Formulation type] The external composition of the present disclosure may be an emulsion preparation such as an oil-in-water emulsion preparation or a water-in-oil emulsion preparation, or may be a non-emulsion preparation such as a solubilized preparation or an aqueous ointment. Originally, when heparin-like substances and allantoin are contained in an emulsion preparation (especially an oil-in-water emulsion preparation), changes in appearance properties (separation of components and accompanying appearance changes) due to storage under non-sealed conditions tend to be remarkable. However, in the external composition of the present disclosure, even if it is an emulsion preparation, changes in appearance properties due to storage under non-sealed conditions can be effectively suppressed. In view of such effects, preferred examples of the external composition of the present disclosure include emulsion preparations, and more preferably oil-in-water emulsion preparations.

[0041] The dosage form of the external composition of the present disclosure is not particularly limited as long as it can be applied transdermally, and it may be in any form such as liquid, semi-solid (cream-like, gel-like, ointment-like, paste-like), solid, etc., but preferably liquid or semi-solid.

[0042] In addition, the external composition of the present disclosure is used as a topical pharmaceutical (including quasi-drugs) or a cosmetic. Specific examples of the dosage form of the external composition of the present invention include creams, lotions, gels, emulsions, liquids, poultices, patches, liniments, aerosols, aqueous ointments, packs, etc. Among these, creams are preferably mentioned.

[0043] [Manufacturing method] The external composition of the present disclosure can be manufactured according to known formulation techniques according to its dosage form. For example, when the external composition of the present disclosure is an emulsion preparation, the components to be contained are divided into water-soluble components and oil components, an aqueous phase containing water-soluble components and an oil phase containing oil components are prepared, and these are emulsified according to known techniques to prepare it.

Examples

[0044] Examples are shown below to more specifically explain the present disclosure, but the present disclosure is not limited thereto.

[0045] Test Example An external composition (cream-type water-in-oil emulsion preparation) having the composition shown in Table 1 was prepared. Specifically, ceramide 2, stearyl alcohol, cetyl alcohol, isopropyl myristate, white petrolatum, liquid paraffin, squalane, dimethylpolysiloxane, propyl paraoxybenzoate, polyoxyethylene hydrogenated castor oil 50, polysorbate 60, and self-emulsifying glyceryl monostearate were mixed in predetermined amounts and heated and dissolved at 75 to 85°C to prepare an oil-phase composition. Separately, a heparin-like substance, allantoin, dipotassium glycyrrhizinate, propylene glycol, 1,3-butylene glycol, sodium edetate hydrate, carboxyvinyl polymer, pH adjuster, methyl paraoxybenzoate, and purified 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, mixed, and subjected to an emulsification operation to obtain an external composition (cream-type water-in-oil emulsion preparation). The external composition immediately after production was in an emulsified state that was white and had no separation.

[0046] Approximately 1 g of the external composition immediately after production was placed on a flat table without being placed in a container and allowed to stand at room temperature for 4 days. The appearance of each external composition after storage was visually observed, and the formulation stability was evaluated according to the following criteria. <Criteria for Formulation Stability> AA: Maintains a white appearance, no separation of components is observed, and there is no difference in appearance properties compared to immediately after preparation. A: Maintains a white appearance, slight separation of components is observed, but there is almost no difference in appearance properties compared to immediately after preparation. B: Slightly changes to a semi-transparent appearance, slight separation of components is also observed, and the appearance properties have changed compared to immediately after preparation. C: Changes to a semi-transparent appearance, separation of components is observed, and the appearance properties have changed significantly compared to immediately after preparation.

[0047] The results are shown in Table 1. In the topical composition containing a heparin-like substance and allantoin, the appearance properties changed significantly after storage under non-sealed conditions (Comparative Example 1). Also, in the topical composition containing either dipotassium glycyrrhizinate or ceramide 2 in addition to the heparin-like substance and allantoin, the appearance properties changed significantly after storage under non-sealed conditions (Comparative Examples 2 and 3). Further, even in the topical composition containing a combination of three components of a heparin-like substance, dipotassium glycyrrhizinate, and ceramide 2, or a combination of three components of allantoin, dipotassium glycyrrhizinate, and ceramide 2, a change in appearance properties was observed after storage under non-sealed conditions (Comparative Examples 4 and 5). In contrast, when a combination of a heparin-like substance, allantoin, dipotassium glycyrrhizinate, and ceramide 2 was included, the change in appearance properties could be suppressed even after storage under non-sealed conditions, and excellent formulation stability was observed (Examples 1 to 3). In particular, in the topical composition containing a heparin-like substance, allantoin, dipotassium glycyrrhizinate, and 0.5 wt% or more of ceramide 2, the change in appearance properties could be significantly suppressed even after storage under non-sealed conditions, and significantly excellent formulation stability was observed (Examples 2 and 3).

[0048] [Table 1]

[0049] Topical compositions (cream-like water-in-oil emulsions) having the compositions shown in Tables 2 and 3 were prepared in the same manner as in the above test example. When the formulation stability of each of the obtained topical compositions was evaluated in the same manner as in the above test example, in each case, the change in appearance properties could be suppressed even after storage under non-sealed conditions, and excellent formulation stability was observed.

[0050] [Table 2]

[0051] [Table 3]

Claims

1. An external composition containing at least one selected from the group consisting of (A) heparin-like substances, (B) allantoin, (C) glycyrrhizic acid, its derivatives, and salts thereof, and (D) ceramide 2.

2. The external composition according to Claim 1, which is an emulsified preparation.

3. The external composition according to Claim 2, which is a cream preparation.

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