Topical composition

Abstract

[Problem] The problem to be addressed by the present disclosure is 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.

Description

External composition

[0001] The present disclosure relates to a composition for external use that contains a heparinoid and allantoin and that can suppress changes in appearance due to storage under unsealed conditions.

[0002] Heparinoids are known to have moisturizing and blood circulation promoting effects, and are used as components of topical compositions. Allantoin has tissue repair activating, anti-inflammatory, and antipruritic effects, and is used as a component of topical compositions.

[0003] In recent years, there has been a strong demand for improving the functionality of topical compositions, and focusing on the functionality of heparinoids and allantoin, topical compositions that improve functionality by combining these components have also been proposed.For example, Patent Document 1 reports that a topical composition that contains a heparinoid, allantoin, and a nonionic surfactant exhibits a melanin production inhibitory effect due to their synergistic effect, and can inhibit, prevent, prevent, or improve skin pigmentation.In addition, Patent Document 2 reports that a topical pharmaceutical composition that contains a heparinoid, allantoin, and panthenol can promote normal differentiation into keratinocytes, increase the area of ​​keratinocytes that constitute the stratum corneum, and normalize the structure and function of the stratum corneum.

[0004] JP 2016-84337 A JP 2011-231128 A

[0005] To commercialize a topical composition, it is necessary to consider not only its efficacy but also its formulation stability. The present inventors have investigated topical compositions containing heparinoids and allantoin from various perspectives and have found that they have problems with formulation stability. Specifically, they have found that storing a topical composition containing heparinoids and allantoin under unsealed conditions results in changes in appearance (separation of components and associated changes in appearance). Topical compositions are usually stored in a sealed state, but since users sometimes forget to close the container lid, it is desirable that the appearance can be maintained stably even when stored under unsealed conditions.

[0006] Therefore, an object of the present disclosure is to provide a composition for external use that contains a heparinoid and allantoin and that can suppress changes in appearance due to storage under unsealed conditions.

[0007] The present inventors have conducted extensive research to solve the above-mentioned problems and have found that changes in appearance due to storage under unsealed conditions can be suppressed by including glycyrrhizic acids and ceramide 2 in a topical composition together with a heparinoid and allantoin. The present disclosure has been completed through further research based on this finding.

[0008] That is, the present disclosure provides topical compositions of the following aspects: Item 1. A topical composition comprising (A) a heparinoid, (B) allantoin, (C) at least one selected from the group consisting of glycyrrhizinic acid, its derivatives, and salts thereof, and (D) ceramide 2. Item 2. The topical composition of claim 1, which is an emulsion preparation. Item 3. The topical composition of claim 2, which is a cream.

[0009] According to the present disclosure, a formulation is provided for an external composition containing a heparinoid and allantoin, which can suppress changes in appearance due to storage under unsealed conditions and provide excellent formulation stability. Although an external composition may be stored under unsealed conditions when a user inadvertently forgets to close the lid of the container, the external composition of the present disclosure can suppress changes in appearance even when stored under unsealed conditions, and therefore can suppress changes in appearance even under such improper storage conditions.

[0010] The topical composition of the present disclosure is characterized by containing (A) a heparinoid, (B) allantoin, (C) at least one selected from the group consisting of glycyrrhizinic acid, its derivatives, and salts thereof, and (D) ceramide 2. The topical composition of the present disclosure is described in detail below. Note that in this disclosure, the expression "X to Y" regarding a numerical range refers to a range from X to Y.

[0011] [(A) Heparinoid] The topical composition of the present disclosure contains a heparinoid (sometimes referred to as component (A)). Heparinoids are polysulfated mucopolysaccharides such as chondroitin polysulfate, and are known components known to have moisturizing and blood circulation-promoting effects. The origin of the heparinoid used in the present disclosure is not particularly limited, but examples include those obtained by polysulfating mucopolysaccharides and those extracted from tissues of edible animals (e.g., bovine lungs, including tracheal cartilage). In the topical composition of the present disclosure, heparinoids listed in the Japanese Pharmacopoeia Non-Drug Standards are preferably used as the heparinoid.

[0012] The content of component (A) in the topical composition of the present disclosure may be set appropriately depending on the intended use, formulation, etc. of the topical composition, but may be, for example, 0.001 to 5 wt %, preferably 0.01 to 1 wt %, more preferably 0.01 to 0.3 wt %, and even more preferably 0.1 to 0.3 wt %.

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

[0014] The content of component (B) in the topical composition of the present disclosure may be set appropriately depending on the intended use, formulation, etc. of the topical composition, but may be, for example, 0.01 to 10 wt %, preferably 0.01 to 8 wt %, more preferably 0.01 to 1 wt %, and even more preferably 0.05 to 0.5 wt %.

[0015] [(C) Glycyrrhizic Acids] The topical composition of the present disclosure contains at least one glycyrrhizic acid (sometimes referred to as component (C)) selected from the group consisting of glycyrrhizic acid, its derivatives, and salts thereof. In the topical composition of the present disclosure, the glycyrrhizic acid has a synergistic effect with ceramide 2, which will be described later, to suppress changes in the appearance of the topical composition containing a heparinoid and allantoin due to storage under unsealed conditions.

[0016] Glycyrrhizic acid is a known drug known to have anti-inflammatory and anti-allergic effects. Derivatives of glycyrrhizic acid are not particularly limited as long as they are pharmaceutically acceptable, and specific examples thereof include methyl glycyrrhizinate, stearyl glycyrrhizinate, etc. Salts of glycyrrhizic acid and its derivatives are not particularly limited as long as they are pharmaceutically acceptable, and specific examples thereof include alkali metal salts such as sodium salts and potassium salts; ammonium salts, etc.

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

[0018] Of these components (C), from the viewpoint of more effectively suppressing changes in appearance due to storage under sealed conditions, salts of glycyrrhizinic acid are preferred, and dipotassium glycyrrhizinate is more preferred.

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

[0020] The content of component (C) in the topical composition of the present disclosure may be set appropriately depending on the intended use, formulation, etc. of the topical composition, but may be, for example, 0.01 to 10 wt %, preferably 0.01 to 2.5 wt %, more preferably 0.1 to 2.5 wt %, and even more preferably 0.5 to 2 wt %.

[0021] [(D) Ceramide 2] The topical composition of the present disclosure contains ceramide 2 (sometimes referred to as component (D)). In the topical composition of the present disclosure, ceramide 2 exerts a synergistic effect with the glycyrrhizic acids, thereby suppressing changes in the appearance of a topical composition containing a heparinoid and allantoin due to storage under unsealed conditions. Ceramide 2 is N-stearoyldihydrosphingosine, a type of human ceramide.

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

[0023] The content of component (D) in the topical composition of the present disclosure may be set appropriately depending on the intended use, formulation, etc. of the topical composition, but may be, for example, 0.001 to 10 wt %, preferably 0.001 to 5 wt %, more preferably 0.05 to 3 wt %, even more preferably 0.1 to 1.5 wt %, particularly preferably 0.3 to 1 wt %, and especially preferably 0.5 to 1 wt %.

[0024] [Water] The topical composition of the present disclosure contains water to prepare it into a desired formulation. The content of water in the topical composition of the present disclosure may be appropriately set depending on the formulation, etc., and may be, for example, 20 to 97 wt %, preferably 25 to 95 wt %, more preferably 30 to 90 wt %, and even more preferably 35 to 80 wt %.

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

[0026] When the topical composition of the present disclosure contains a polyhydric alcohol, the content thereof is not particularly limited, but may be, for example, 0.1 to 25% by weight, preferably 1 to 20% by weight, and more preferably 2 to 15% by weight.

[0027] [Surfactant] The topical composition of the present disclosure may contain a surfactant to prepare it into a desired formulation. 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 nonionic surfactant is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbit fatty acid esters, polyoxyethylene alkyl ethers, polyethylene glycol fatty acid esters, and lecithin derivatives. Among these, preferred examples of nonionic surfactants include polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, and glycerin fatty acid esters. These nonionic surfactants may be used alone or in combination of two or more.

[0029] When a surfactant is contained in the topical composition of the present disclosure, the content thereof may be appropriately set depending on the formulation, the type of surfactant used, etc., and may be, for example, 0.1 to 20% by weight, preferably 0.5 to 10% by weight, and more preferably 1 to 5% by weight.

[0030] [Thickener] The topical composition of the present disclosure may contain a thickener as needed to impart viscosity, etc. The type of thickener is not particularly limited as long as it is pharmaceutically acceptable, but examples include carboxyvinyl polymer, xanthan gum, guar gum, locust bean gum, carrageenan, dextran, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium alginate, propylene glycol alginate, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, acrylic acid alkyl methacrylate copolymer, sodium polyacrylate bentonite, dextrin fatty acid ester, pectin, etc. Among these thickeners, carboxyvinyl polymer is preferred. These thickeners may be used alone or in combination of two or more.

[0031] When a thickener is contained in the topical composition of the present disclosure, the content thereof is not particularly limited, but may be, for example, 0.05 to 5 wt %, preferably 0.1 to 3 wt %, and more preferably 0.1 to 1 wt %.

[0032] [Chelating Agent] The topical composition of the present disclosure may contain a chelating agent as needed. The type of chelating agent is not particularly limited as long as it is pharmaceutically acceptable, but examples include 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. Among these thickeners, edetic acid and its salts are preferred, and sodium edetate is more preferred. These chelating agents may be used alone or in combination of two or more.

[0033] When a chelating agent is contained in the topical composition of the present disclosure, the content thereof is not particularly limited, but may be, for example, 0.001 to 5 wt %, preferably 0.01 to 1 wt %, and more preferably 0.05 to 0.5 wt %.

[0034] [Oil] The topical composition of the present disclosure may contain oil to prepare it into a desired formulation. The type of oil is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include higher monohydric alcohols, fatty acid alkyl esters, hydrocarbon oils, silicone oils, vegetable oils, animal oils, cholesterol, etc.

[0035] Among these oils, preferred examples include monohydric higher alcohols, fatty acid alkyl esters, hydrocarbon oils, and silicone oils. Examples of monohydric higher alcohols include monohydric alcohols having 12 to 34 carbon atoms, specifically myristyl alcohol, cetyl alcohol, oleyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol, hexadecyl alcohol, and lanolin alcohol. Examples of fatty acid alkyl esters 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, and ethyl oleate. Specific examples of hydrocarbon oils include paraffin, hydrogenated polyisobutene, liquid paraffin, gelled hydrocarbons (such as Plastibase), ceresin, microcrystalline wax, white petrolatum, and squalane. Specific examples of silicone oils include methylpolysiloxane, dimethylpolysiloxane, cyclic silicone, alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, acrylic silicone, and phenyl-modified silicone.

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

[0037] When oil is contained in the topical composition of the present disclosure, the content thereof may be set appropriately depending on the formulation, etc., and may be, for example, 1 to 60% by weight, preferably 5 to 50% by weight, more preferably 5 to 40% by weight, and even more preferably 10 to 30% by weight.

[0038] [Other components] In addition to the above-mentioned components, the topical composition of the present disclosure may contain other commonly used additives as needed.Such additives include preservatives, monohydric lower alcohols, pH adjusters, buffers, solubilizers, antioxidants, stabilizers, fragrances, colorants, etc.When these additives are contained in the topical composition of the present disclosure, their content can be appropriately set according to the type of additives used, etc.

[0039] In addition, the topical composition of the present disclosure may contain pharmacological ingredients in addition to the above-mentioned ingredients. Examples of such pharmacological ingredients include antihistamines, local anesthetics, moisturizers, disinfectants, antibacterial agents, antipruritics, skin protectants, blood circulation promoters, vitamins, etc. These pharmacological ingredients may be used alone or in combination of two or more. Furthermore, when these pharmacological ingredients are contained in the topical composition of the present disclosure, their concentrations may be appropriately determined depending on the type of pharmacological ingredient used, the desired effect, etc.

[0040] [Formulation and dosage form] The topical composition of the present disclosure may be an emulsion formulation such as an oil-in-water emulsion formulation or a water-in-oil emulsion formulation, or may be a non-emulsified formulation such as a solubilized formulation or an aqueous ointment. In general, when heparinoids and allantoin are contained in an emulsion formulation (especially an oil-in-water emulsion formulation), changes in appearance (separation of components and associated changes in appearance) tend to be significant when stored under unsealed conditions. However, the topical composition of the present disclosure can effectively suppress changes in appearance when stored under unsealed conditions, even when the composition is an emulsion formulation. In view of these effects, the topical composition of the present disclosure is preferably an emulsion formulation, more preferably an oil-in-water emulsion formulation.

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

[0042] The topical composition of the present disclosure is used as a topical skin drug (including quasi-drugs) or cosmetic. Specific examples of the formulation of the topical composition of the present invention include creams, lotions, gels, emulsions, liquids, poultices, patches, liniments, aerosols, aqueous ointments, and packs. Of these, creams are preferred.

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

[0044] The present disclosure will be explained in more detail below by showing examples, but the present disclosure is not limited to these examples.

[0045] Test Example: A topical composition (cream-like oil-in-water emulsion preparation) with the composition shown in Table 1 was prepared. Specifically, an oil phase composition was prepared by mixing predetermined amounts of ceramide 2, stearyl alcohol, cetanol, isopropyl myristate, white petrolatum, liquid paraffin, squalane, dimethylpolysiloxane, propyl parahydroxybenzoate, polyoxyethylene hydrogenated castor oil 50, polysorbate 60, and self-emulsifying glyceryl monostearate and dissolving the mixture by heating at 75 to 85°C. Separately, an aqueous phase composition was prepared by mixing predetermined amounts of a heparinoid, allantoin, dipotassium glycyrrhizinate, propylene glycol, 1,3-butylene glycol, sodium edetate hydrate, carboxyvinyl polymer, pH adjuster, methyl parahydroxybenzoate, and purified water. 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, thereby obtaining a topical composition (a creamy oil-in-water emulsion preparation). The topical composition immediately after production was white and in an emulsified state without separation.

[0046] Approximately 1 g of the topical composition immediately after preparation 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 topical composition after storage was visually observed, and the formulation stability was evaluated according to the following criteria. <Criteria for determining formulation stability> AA: The white appearance was maintained, no separation of ingredients was observed, and no difference in appearance was observed compared to immediately after preparation. A: The white appearance was maintained, and slight separation of ingredients was observed, but almost no difference in appearance was observed compared to immediately after preparation. B: The appearance changed to a slightly translucent one, and slight separation of ingredients was observed, resulting in a change in appearance compared to immediately after preparation. C: The appearance changed to a translucent one, and separation of ingredients was observed, resulting in a significant change in appearance compared to immediately after preparation.

[0047] The results are shown in Table 1. The external appearance of a topical composition containing a heparinoid and allantoin changed significantly after storage under unsealed conditions (Comparative Example 1). Furthermore, the external appearance of a topical composition containing, in addition to a heparinoid and allantoin, either dipotassium glycyrrhizinate or ceramide 2 also changed significantly after storage under unsealed conditions (Comparative Examples 2 and 3). Furthermore, the external appearance of a topical composition containing a combination of three components (heparinoid, dipotassium glycyrrhizinate, and ceramide 2) or allantoin, dipotassium glycyrrhizinate, and ceramide 2 also changed after storage under unsealed conditions (Comparative Examples 4 and 5). In contrast, when a combination of a heparinoid, allantoin, dipotassium glycyrrhizinate, and ceramide 2 was contained, changes in external appearance were suppressed even after storage under unsealed conditions, demonstrating excellent formulation stability (Examples 1 to 3). In particular, the topical compositions containing heparinoids, allantoin, dipotassium glycyrrhizinate, and 0.5% by weight or more of ceramide 2 were able to significantly suppress changes in appearance even after storage under unsealed conditions, demonstrating significantly excellent formulation stability (Examples 2 and 3).

[0048]

[0049] Topical compositions (creamy oil-in-water emulsion preparations) with the compositions shown in Tables 2 and 3 were prepared in the same manner as in the above-mentioned Test Examples. The stability of each of the obtained topical compositions was evaluated in the same manner as in the above-mentioned Test Examples. All of the compositions showed no change in appearance even after storage under unsealed conditions, demonstrating excellent formulation stability.

[0050]

[0051]

Claims

1. A composition for external use comprising (A) a heparinoid, (B) allantoin, (C) at least one selected from the group consisting of glycyrrhizinic acid, its derivatives, and salts thereof, and (D) ceramide 2.

2. The topical composition according to claim 1, which is an emulsion preparation.

3. The topical composition according to claim 2, which is a cream.

Images