External components

Abstract

To provide an external composition that can improve a skin barrier function.SOLUTION: An external composition containing (A) ceramide and (B) carnitine, a salt thereof, and / or a derivative thereof can effectively promote the maturation of CE and is effective in improving a skin barrier function.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an external composition capable of improving the skin barrier function.

Background Art

[0002] The epidermis is composed of four layers: the basal layer, the spinous layer, the granular layer, and the stratum corneum. The stratum corneum is composed of corneocytes and intercellular lipids that fill the gaps between them, and plays an important role as a skin barrier that protects living cells in the body. Corneocytes gradually differentiate from the basal layer and move toward the skin surface side, and finally become keratinocytes to form the stratum corneum. In the process of differentiating into corneocytes, the production of precursor proteins (involucrin, loricrin, etc.) of the cornified envelope (Cornified Envelope) begins in the spinous layer, and the precursor proteins become CE in the upper part of the granular layer. CE forms an inner lining structure of the cell membrane by being cross-linked and insolubilized by transglutaminase, and gradually matures and reaches the stratum corneum, replacing the disappearing cell membrane and becoming the outer wall of keratinocytes. Furthermore, CE becomes a strong protein bag that wraps corneocytes by fully maturing in the stratum corneum.

[0003] CE plays a role in the normal function of the stratum corneum, and promoting the maturation of CE is important for enabling a normal skin barrier function. Therefore, conventionally, external compositions capable of improving the skin barrier function have been studied by focusing on promoting the maturation of CE. For example, Patent Document 1 discloses that astaxanthin and Haematococcus algae extract have an effect of promoting CE maturation. In addition, Patent Document 2 reports that specific pyrrolidone derivatives and / or their salts have an effect of promoting the formation or maturation of CE. Further, Patent Document 3 reports that acidic xylooligosaccharide has an effect of promoting the expression of involucrin and keratin 10, which are constituent proteins of CE, and can be used as an epidermal keratinization normalizing agent.

[0004] On the other hand, ceramides have traditionally been known as moisturizing components in the intercellular lipids of the stratum corneum, and various topical compositions containing ceramides have been commercialized. However, simply supplying ceramides from the outside is not sufficient to promote the maturation of CE, and its effect on improving skin barrier function is limited. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Japanese Patent Publication No. 2012-153637 [Patent Document 2] Japanese Patent Publication No. 2008-303185 [Patent Document 3] Japanese Patent Publication No. 2009-143832 [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] The object of the present invention is to provide a topical composition that can improve the skin barrier function. [Means for solving the problem]

[0007] The inventors of the present invention conducted diligent research to solve the aforementioned problems and found that a topical composition comprising (A) ceramide and (B) carnitine, its salts, and / or derivatives thereof can promote the maturation of CE, effectively construct a barrier structure with CE and intercellular lipids, and has an excellent effect in improving skin barrier function. The present invention was completed by further research based on these findings.

[0008] In other words, the present invention provides inventions in the following embodiments. Item 1. A topical composition comprising (A) ceramide and (B) at least one selected from the group consisting of carnitine, its salts, and derivatives thereof. Item 2. The topical composition according to Item 1, comprising two or more ceramides as component (A). Item 3. The topical composition according to item 1 or 2, wherein component (A) is two or more selected from the group consisting of ceramide 1, ceramide 2, and ceramide 3. Item 4. The topical composition according to any one of items 1 to 3, wherein component (B) is L-carnitine. Item 5. An external composition according to any one of items 1 to 4, further comprising a surfactant. [Effects of the Invention]

[0009] The topical composition of the present invention can improve a weakened skin barrier function, maintain a healthy skin barrier function, and suppress the decline of the skin barrier function. Furthermore, it can prevent or treat skin diseases such as atopic dermatitis, xerosis, and senile xerosis caused by a weakened skin barrier function. Moreover, by promoting the maturation of CE, the topical composition of the present invention can improve or normalize the condition of the skin, improve rough skin, improve sensitive skin, and prevent skin aging. [Brief explanation of the drawing]

[0010] [Figure 1] This figure shows the results of calculating the difference in transepidermal water loss (TEWL) (ΔTEWL) before and after the test using a human epidermal model. [Modes for carrying out the invention]

[0011] The topical composition of the present invention is characterized by containing ceramide (sometimes referred to as component (A)) and at least one selected from the group consisting of carnitine, its salts, and derivatives thereof (sometimes referred to as component (B)). The topical composition of the present invention will be described in detail below.

[0012] [(A) Ceramide] The topical composition of the present invention contains ceramide. Ceramide is a compound in which a fatty acid is bonded to the amino group of sphingosine or phytosphingosine by an amide bond.

[0013] In the ceramide used in the present invention, the type of fatty acid bonded to the amino group of sphingosine or phytosphingosine is not particularly limited and may be any fatty acid without a hydroxyl group, α-hydroxy fatty acid, ω-hydroxy fatty acid, etc.

[0014] Examples of ceramides used in the present invention include ceramide 1, ceramide 2, ceramide 3, ceramide 4, ceramide 5, ceramide 6I, ceramide 6II, ceramide 7, ceramide 8, ceramide 9, ceramide 10, and the like.

[0015] In the topical composition of the present invention, component (A) may be a single ceramide or a combination of two or more ceramides. In particular, using a combination of two or more ceramides in the topical composition of the present invention makes it possible to further improve the effect of improving the skin barrier function.

[0016] When using two or more types of ceramides, there are no particular restrictions on the combination of ceramides, but from the viewpoint of further improving the effect of improving the skin barrier function, a combination of two or more types from ceramide 1, ceramide 2, and ceramide 3 is preferred, and a combination of three types from ceramide 1, ceramide 2, and ceramide 3 is more preferred.

[0017] (A) When using a combination of two types of ceramides, ceramide 1 and ceramide 2, as components, there are no particular restrictions on the ratio of these ceramides, but for example, the weight ratio of ceramide 2 to ceramide 1 is 1:0.00000002 to 10000, preferably 1:0.00000003 to 10000, more preferably 1:0.00000003 to 1, and even more preferably 1:0.0001 to 0.01.

[0018] When using a combination of two types of ceramides, ceramide 1 and ceramide 3, as component (A), the ratio of these ceramides is not particularly limited. For example, the weight ratio of ceramide 3:ceramide 1 can be 1:0.0000001 to 10000, preferably 1:0.0000002 to 10000, more preferably 1:0.0000002 to 10, and even more preferably 1:0.0001 to 0.01.

[0019] When using a combination of two types of ceramides, ceramide 2 and ceramide 3, as component (A), the ratio of these ceramides is not particularly limited. For example, the weight ratio of ceramide 3:ceramide 2 can be 1:0.00001 to 400000, preferably 1:0.02 to 400000, more preferably 1:0.02 to 40000, and even more preferably 1:0.1 to 10.

[0020] When using a combination of three types of ceramides, ceramide 1, ceramide 2, and ceramide 3, as component (A), the ratio of these ceramides is not particularly limited. For example, the weight ratio of ceramide 1:ceramide 2:ceramide 3 can be 0.0000001 to 10000:0.00001 to 400000:1, preferably 0.0000002 to 10000:0.02 to 400000:1, more preferably 0.0000002 to 10:0.02 to 40000:1, and even more preferably 0.1 to 10:100 to 10000:1.

[0021] The content of component (A) in the external composition of the present invention may be appropriately set according to the dosage form of the external composition, etc. For example, the total amount of component (A) can be 0.0000001 to 5.5% by weight, preferably 0.001 to 4.5% by weight, and more preferably 0.01 to 4.5% by weight. The content of component (A) in the external composition of the present invention may be appropriately set according to the dosage form of the external composition, etc. For example, the total amount of component (A) can be 0.0000001 to 5.5% by weight, preferably 0.001 to 4.5% by weight, and more preferably 0.01 to 4.5% by weight.

[0022] [(B) Carnitine, its salts, and / or its derivatives] The topical composition of the present invention contains, in addition to ceramide, carnitine, its salts, and / or derivatives thereof. By using ceramide and carnitine in combination in this way, the maturation of CE can be effectively promoted, and an excellent improvement in skin barrier function can be achieved.

[0023] Carnitine is a vitamin-like substance synthesized from lysine and methionine. In this invention, any of L-carnitine, D-carnitine, levocarnitine, and DL-carnitine may be used as carnitine, but L-carnitine, DL-carnitine, and more preferably L-carnitine are used.

[0024] There are no particular restrictions on carnitine salts, as long as they are pharmaceutically or cosmetically acceptable, but examples include halide salts, metal salts, ammonium salts, organic acid salts, and inorganic acid salts. More specifically, carnitine salts include chloride salts; metal salts such as sodium salts, potassium salts, calcium salts, magnesium salts, and zinc salts; ammonium salts; organic acid salts such as acetate, propionate, lactate, tartrate, citrate, succinate, maleate, and fumarate; and inorganic acid salts such as hydrochloride, sulfate, and phosphate.

[0025] Carnitine derivatives are not particularly limited as long as they are pharmaceutically or cosmetically acceptable, but examples include esters of carnitine such as acetylcarnitine, butyrylcarnitine, valerylcarnitine, isovalerylcarnitine, propylcarnitine, and propionylcarnitine.

[0026] In the topical composition of the present invention, one of carnitine, its salts, and their derivatives may be selected as component (B) and used alone, or two or more of these may be used in combination. From the viewpoint of further improving the effect of improving the skin barrier function, carnitine, and more preferably L-carnitine, are cited as component (B).

[0027] The content of component (B) in the topical composition of the present invention may be set appropriately depending on the formulation form of the topical composition, but for example, the total amount of component (B) may be 0.00001 to 10% by weight, preferably 0.0001 to 10% by weight, and more preferably 0.001 to 10% by weight.

[0028] In the external composition of the present invention, the ratio of component (B) to component (A) can be appropriately set within the range that satisfies the content of both components as described above. For example, per 1 part by weight of the total amount of component (A), the total amount of component (B) may be 0.000001 to 500000 parts by weight, preferably 0.000002 to 50000 parts by weight, more preferably 0.00002 to 5000 parts by weight, and even more preferably 1 to 100 parts by weight.

[0029] [Surfactants] The topical composition of the present invention may contain a surfactant. Conventionally, surfactants are often added to topical compositions to emulsify or solubilize the contained components, but surfactants added to topical compositions can delay the maturation of CE or reduce the skin barrier function. In contrast, even if the topical composition of the present invention contains a surfactant, the effects of components (A) and (B) outweigh the aforementioned drawbacks of the surfactant, resulting in an excellent improvement in skin barrier function.

[0030] The surfactant used in the present invention is not particularly limited to the extent that it is pharmaceutically or cosmetically acceptable, and may be any of nonionic surfactants, anionic surfactants, cationic surfactants, or amphoteric surfactants.

[0031] Examples of nonionic surfactants include polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, polyoxyethylene polyoxypropylene alkyl ether, glycerin fatty acid ester, polyglycerin fatty acid ester, sucrose fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene alkyl ether, and lecithin derivatives.

[0032] Furthermore, specific examples of anionic surfactants include sodium polyoxyethylene lauryl ether sulfate, sodium lauryl sulfate, sodium myristyl sulfate, sodium N-lauroyl sarcosinate, sodium N-myristoyl sarcosinate, sodium dodecylbenzenesulfonate, hydrogenated coconut fatty acid monoglyceride monosulfate, sodium lauryl sulfoacetate, sodium α-olefin sulfonate, sodium N-palmitoyl glutarmate, and sodium N-methyl-N-acyl taurate.

[0033] Examples of cationic surfactants include lauryltrimethylammonium chloride, stearyltrimethylammonium chloride, benzethonium chloride, benzalkonium chloride, and stearyldimethylbenzylammonium chloride.

[0034] Examples of amphoteric surfactants include coconut oil fatty acid amidopropyl betaine, lauryldimethylaminoacetic acid betaine, lauryldimethylamine oxide, 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolium betaine, N-lauryldiaminoethylglycine, N-myristyldiaminoethylglycine, sodium N-alkyl-1-hydroxyethylimidazoline betaine, and lecithin.

[0035] These surfactants may be used individually or in combination of two or more.

[0036] In conventional technology, nonionic surfactants (particularly polyoxyethylene hydrogenated castor oil) tend to have a strong effect of delaying the maturation of CE and reducing skin barrier function. However, the topical composition of the present invention can achieve excellent improvement of skin barrier function even when containing nonionic surfactants such as polyoxyethylene hydrogenated castor oil. Considering these effects of the present invention, a preferred example of a surfactant is a nonionic surfactant, particularly polyoxyethylene hydrogenated castor oil.

[0037] When a surfactant is included in the topical composition of the present invention, the amount can be appropriately set depending on the formulation of the topical composition, the type of surfactant used, etc., but for example, 0.0001 to 30% by weight, preferably 0.0001 to 10% by weight, and more preferably 0.001 to 10% by weight.

[0038] In particular, as mentioned above, nonionic surfactants tend to delay the maturation of CE and impair skin barrier function, and this tendency tends to become stronger as their content increases (especially 0.5% by weight or more, preferably 1-10% by weight). However, even when the topical composition of the present invention contains nonionic surfactants at such concentrations, it can still achieve excellent skin barrier function improvement effects.

[0039] [Other ingredients] In addition to the components described above, the topical composition of the present invention may optionally contain pharmacoactive ingredients that can exert pharmaceutical or cosmetic physiological functions. Examples of such pharmacoactive ingredients include steroids, antihistamines, local anesthetics, anti-inflammatory agents, bactericides, antibacterial agents, antipruritics, skin protectants, blood circulation promoting ingredients, vitamins, mucopolysaccharides, and the like. These pharmacoactive ingredients may be used individually or in combination of two or more. Furthermore, when these pharmacoactive ingredients are included in the topical composition of the present invention, their concentrations may be appropriately set according to the type of pharmacoactive ingredient used, the expected effect, etc.

[0040] Furthermore, in addition to the components described above, the topical composition of the present invention may contain other additives commonly used in topical compositions, as needed. Examples of such additives include aqueous bases (water, buffer solutions, monohydric lower alcohols, polyhydric alcohols, etc.), solubilizers, oily bases, oils (animal oils, vegetable oils, mineral oils, waxes, waxes, ester oils, fatty acid alkyl esters, higher fatty acids, monohydric higher alcohols, silicone oils, cholesterol, etc.), thickeners, chelating agents, preservatives, antioxidants, stabilizers, chelating agents, fragrances, colorants, and the like. When these additives are included in the topical composition of the present invention, their content may be appropriately determined depending on the type of additive used.

[0041] [Dosage Form / Form of Preparation] The dosage form of the topical composition of the present invention is not particularly limited, as long as it is applicable transdermally, and may be liquid, solid, or semi-solid (cream, gel, ointment, paste, etc.). Furthermore, the topical composition of the present invention may be an emulsified formulation such as an oil-in-water emulsion or a water-in-oil emulsion, or a non-emulsified formulation such as a solubilized formulation or an aqueous ointment.

[0042] Furthermore, the topical composition of the present invention may be in any formulation form, such as a topical drug for skin, a cosmetic, or a skin cleanser, as long as it is applied to the skin.

[0043] Examples of formulations of the topical composition of the present invention include topical skin pharmaceuticals such as creams, lotions, gels, emulsions, liquids, poultices, patches, liniments, aerosols, ointments, and packs; cosmetics such as ointments, creams, emulsions, lotions, packs, and gels; and skin cleansing products such as body shampoos, hair shampoos, and conditioners.

[0044] [Applications / How to use] The topical composition of the present invention can improve skin barrier function and is therefore used for improving skin barrier function, such as enhancing impaired skin barrier function, maintaining healthy skin barrier function, and suppressing the decline of skin barrier function.

[0045] Furthermore, the topical composition of the present invention can prevent or treat skin diseases caused by a decrease in skin barrier function by improving the skin barrier function, and can therefore be used as a preventive or therapeutic agent for such skin diseases. Specific examples of skin diseases caused by a decrease in skin barrier function include atopic dermatitis, xerosis, and senile xerosis.

[0046] Furthermore, since the topical composition of the present invention can promote the maturation of cerebrospinal fluid (CE), it can also be used for CE maturation promotion purposes. In addition, since promoting CE maturation can reduce transepidermal water loss (TEWL), the topical composition of the present invention can also be used for reducing transepidermal water loss. Moreover, by promoting CE maturation, the topical composition of the present invention can improve or normalize skin condition, improve rough skin, improve sensitive skin, and prevent skin aging, so it can also be used for skincare purposes.

[0047] The topical composition of the present invention is used by applying or spraying an appropriate amount onto skin where improvement of the skin barrier function is required. The amount of the topical composition of the present invention applied to the skin may be appropriately determined depending on the dosage form, formulation, the severity of the symptoms being treated, etc. For example, 1 cm² of skin 2 In that case, an external composition corresponding to approximately 0.00001 to 10 mg in terms of the amount of (A) component should be applied. [Examples]

[0048] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0049] Test Example 1 Skin barrier function was evaluated by measuring changes in TEWL using a human epidermal model. The human epidermal model used was "LabCyte EPI-MODEL24 6D" (Japan Tissue Engineering Co., Ltd.). This human epidermal model is a 24-well three-dimensional cultured human epidermal model formed by layering human normal epidermal cells for 6 days in a culture cup with a membrane filter at the bottom. It has an initial (immature) stratum corneum, an immature CE, and epidermal tissue with high TEWL values. The specific test method is described below.

[0050] First, 0.5 ml of the dedicated assay medium was added to each well of the "LabCyte EPI-MODEL24 6D" assay plate. Then, a culture cup was attached to each well, and the cells were incubated at 36°C for 24 hours. After 24 hours of incubation, the TEWL of each well was measured using a TEWL analyzer (Tewitro TW24, Courage+Khazaka) capable of simultaneously measuring TEWL in all 24 wells (initial TEWL value).

[0051] Separately, a mixture containing predetermined amounts of various ceramides, L-carnitine, polyoxyethylene hydrogenated castor oil 60, oleic acid, butylene glycol, and purified water was prepared and added to a dedicated assay medium to achieve the composition shown in Table 1 to create the test medium. Next, the culture medium was removed from each well of the assay plate after 24 hours of incubation, and the test medium prepared above was added at a concentration of 0.5 ml / well. Then, culture cups were attached to each well, and incubation was carried out at 36°C for 120 hours. After 120 hours of incubation, TEWL was measured for each well using a TEWL measuring instrument (Tewitro TW24, Courage+Khazaka) (TEWL value after 120 hours). The ΔTEWL value was calculated by subtracting the TEWL value after 120 hours from the initial TEWL value. In addition, as an untreated control, the same test was performed using a dedicated assay medium (without added components) instead of the test medium, and the ΔTEWL value was determined. This test was performed under the condition of n=4.

[0052] [Table 1]

[0053] The results obtained are shown in Figure 1. In Comparative Example 1, which did not contain ceramide or L-carnitine, ΔTEWL was smaller than that of the untreated control. This is thought to be due to the surfactant (polyoxyethylene hydrogenated castor oil) contained in the test medium used in Comparative Example 1, which delayed the maturation of CE and inhibited the expression of skin barrier function. Furthermore, in Comparative Examples 2 to 9, which contained only ceramide or L-carnitine, ΔTEWL was larger than that of Comparative Example 1, but smaller than that of the untreated control, and sufficient expression of skin barrier function was not observed. In contrast, in Examples 1 to 9, which contained both ceramide and L-carnitine, a higher ΔTEWL was observed than that of the untreated control. That is, the combined use of ceramide and L-carnitine promoted the maturation of CE and enabled the expression of excellent barrier function. In particular, when two or more types of ceramide were combined with L-carnitine (especially when ceramides 1, 2, and 3 were combined with L-carnitine), ΔTEWL was significantly higher, and a remarkable improvement in skin barrier function was observed.

[0054] Prescription examples Table 2 shows the oil-in-water emulsion topical compositions that were prepared. The use of these topical compositions is expected to improve skin barrier function by promoting the maturation of cerebrospinal fluid (CE).

[0055] [Table 2]

Claims

1. (A) Ceramide, (B) L-carnitine, and polyoxyethylene hydrogenated castor oil are included. (A) per 1 part by weight of total ceramide, (B) carnitine is 1 to 100 parts by weight. External compositions in liquid, cream, gel, or paste form (excluding those containing at least one selected from rhododendrol and its derivatives represented by the following general formula (1), those containing benzophenone, those containing tocopherol, and those containing coralline algae extract (corallina officinalis extract)). 【Chemistry 1】 (In the formula, R is a hydrogen atom, an acyl group having 2 to 20 carbon atoms, or a sugar residue of a monosaccharide or disaccharide.)

2. (A) The topical composition according to claim 1, comprising two or more ceramides as components.

3. (A) The topical composition according to claim 1 or 2, wherein the component is two or more selected from the group consisting of ceramide 1, ceramide 2, and ceramide 3.

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