Topical composition for xeroderma treatment

Abstract

To provide a water-in-oil emulsion composition with superior moisturizing and protective effects for the purpose of alleviating and healing xerodermic conditions, and further to provide a dermatological topical agent that delivers a high healing effect in a short time.SOLUTION: An oil-in-water emulsion composition is prepared that contains human-type ceramides delivering a healing effect against xerodermic conditions in a short time, in addition to the moisturizing effect of heparinoids. The oil-in-water emulsion composition enables the production of a dermatological topical agent that delivers a high healing effect against xerodermic conditions in a short time, while overcoming the drawbacks of water-in-oil creams.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an external skin lining agent which uses a heparinoid, and in particular to an external skin lining agent which is highly effective in treating xeroderma. [Background technology]

[0002] Heparinoids are a type of polysaccharide that have many hydrophilic groups such as sulfate, hydroxyl, and carboxyl groups in their molecular structure and have excellent moisturizing effects, so they are widely used in the treatment of dry skin diseases such as xerosis. In particular, they are often used as water-in-oil creams for the purpose of moisturizing and protecting the affected area at the same time.

[0003] Since the continuous phase of the emulsion composition of water-in-oil cream is oil phase, it is considered to be highly effective in suppressing water evaporation and protecting the affected area from drying. However, since water-in-oil cream is a thermodynamically unstable system, it is prone to dehydration due to emulsion destruction. In addition, there is a problem that it takes a long time for the symptoms of xerosis to improve based on the moisturizing effect of the heparinoid in the water-in-oil cream.

[0004] In addition, while water-in-oil creams offer high protective power, because the continuous phase is an oil phase, they are forced to use oils and fats that do not mix well with the skin, which results in issues with the feel of oiliness when used. In addition, some ingredients may have reduced skin penetration, so there is a demand for oil-in-water creams.

[0005] Xeroderma (asteatotic dermatitis) is a condition caused by a decrease in the body's ability to retain moisture and resistance to external stimuli due to a decrease in the skin's barrier function caused by factors such as a decrease in sebum secretion, a decrease in intercellular lipids such as ceramide, and a decrease in natural moisturizing factors. It is also suggested that it is accompanied by itching due to irritability of intraepidermal nerve fibers, and that the decrease in the skin's barrier function makes it easier for environmental antigens to penetrate, leading to a delayed-type allergic reaction.

[0006] To treat this condition, moisturizing topical preparations (e.g., urea-containing creams, heparinoid-containing creams) or steroid-containing topical preparations are applied in multiple layers, and when the itching is severe, anti-allergy drugs are taken orally. One of the treatments for xerosis is the application of ceramide-containing topical preparations. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Masukawa, Y., et al., J. Lipid Res. 2008. 49: 1466-1476 [Non-Patent Document 2] Robson, KJ, et al., J. Lipid Res. 1994. 35: 2060-2068 Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention aims to provide an oil-in-water emulsion composition having excellent moisturizing and protective effects for the purpose of improving and curing the symptoms of xerosis, and further to provide an external application for the skin that can exert a high curative effect in a short period of time. [Means for solving the problem]

[0009] In order to solve the above problems, the present invention provides an oil-in-water emulsion composition containing human ceramide, which has a short-term healing effect on the symptoms of xerosis in addition to the moisturizing effect of a heparinoid, thereby providing an external skin application agent that can exert a high short-term healing effect on the symptoms of xerosis while eliminating the drawbacks of water-in-oil creams.

[0010] More specifically, in order to solve the above-mentioned problems, the present application provides the following aspects: [1]: An oil-in-water emulsion composition containing a heparinoid and N-stearoyldihydrosphingosine; [2]: The composition for external use on the skin according to [1], wherein the content of the heparinoid is 0.1 to 0.5% by mass and the content of the N-stearoyldihydrosphingosine is 0.1 to 1% by mass; [3]: The skin topical application preparation according to [1] or [2], further comprising one to three components selected from the group consisting of panthenol, tocopherol acetate, and dipotassium glycyrrhizinate; [4]: The skin topical application preparation according to [3], wherein the panthenol content is 1 to 10 mass%, the tocopherol acetate content is 0.05 to 3.0 mass%, and the dipotassium glycyrrhizinate content is 0.1 to 2 mass%; [5]: an oil-in-water emulsion composition containing a heparinoid, N-stearoyldihydrosphingosine and hydrogenated soybean phospholipid; [6]: The composition for external use on the skin according to [5], wherein the content of the heparinoid is 0.1 to 0.5% by mass, the content of the N-stearoyldihydrosphingosine is 0.1 to 1% by mass, and the content of the hydrogenated soybean phospholipid is 0.1 to 1% by mass; [7]: The skin topical application preparation according to [5] or [6], further comprising one to three components selected from the group consisting of panthenol, tocopherol acetate, and dipotassium glycyrrhizinate; [8]: The skin topical application preparation according to [7], wherein the panthenol content is 1 to 10 mass%, the tocopherol acetate content is 0.05 to 3.0 mass%, and the dipotassium glycyrrhizinate content is 0.1 to 2 mass%; [9]: A skin topical application for treating xerosis, comprising an oil-in-water emulsion composition containing a heparinoid and N-stearoyldihydrosphingosine, or an oil-in-water emulsion composition containing a heparinoid, N-stearoyldihydrosphingosine, and hydrogenated soybean phospholipid;

[10] : The skin topical application preparation according to [9], wherein the heparinoid content is 0.1 to 0.5% by mass, the N-stearoyldihydrosphingosine content is 0.1 to 1% by mass, and the hydrogenated soybean phospholipid content is 0.1 to 1% by mass;

[11] : The skin topical application preparation according to [9] or

[10] , further comprising one to three components selected from the group consisting of panthenol, tocopherol acetate, and dipotassium glycyrrhizinate;

[12] : The external skin application preparation according to

[11] , wherein the panthenol content is 1 to 10 mass %, the tocopherol acetate content is 0.05 to 3.0 mass %, and the dipotassium glycyrrhizinate content is 0.1 to 2 mass %. Effect of the Invention

[0011] The present invention provides an oil-in-water emulsion composition containing human ceramide, which has a short-term healing effect on the symptoms of xerosis in addition to the moisturizing effect of a heparinoid, thereby providing an external skin application agent that can exert a high short-term healing effect on the symptoms of xerosis while eliminating the drawbacks of water-in-oil creams. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 shows the results of measuring the moisture content of the stratum corneum one hour after application of each cream. [Diagram 2] FIG. 2 shows the results of measuring the amount of transepidermal water loss one hour after application of each cream. [Diagram 3] FIG. 3 shows the results of measuring the moisture content of the stratum corneum after washing and drying of the measurement site 3 hours after application of the cream. [Figure 4] FIG. 4 shows the results of measuring transepidermal water loss after washing and drying the measurement site 3 hours after application of the cream. [Diagram 5] FIG. 5 shows the results of measuring the transepidermal water loss one hour after application of the oil-in-water cream of the present invention (Preparation Example 2) to which an additional medicinal ingredient was further added (Preparation Example 3). [Figure 6] FIG. 6 shows the results of measuring transepidermal water loss one hour after application of the cream for a preparation not containing any of the active ingredients of the present invention. [Figure 7]FIG. 7 shows the results of measuring the moisture content of the stratum corneum over time when the cream of the present invention was applied continuously. [Figure 8] FIG. 8 shows the results of measuring transepidermal water loss over time when the cream of the present invention was applied continuously. [Figure 9-1] FIG. 9-1 is a histological image showing the change over time in skin tissue after application of the oil-in-water emulsion composition of the present invention. [Figure 9-2] For comparison, FIG. 9-2 is a tissue image showing the stratum corneum of a healthy subject who does not feel that his skin is dry. [Figure 10] FIG. 10 is a histology image showing the change over time in the appearance of a subject's skin when the oil-in-water emulsion composition of the present invention was applied. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] As a result of intensive research to solve the above-mentioned problems, the inventors of the present invention have demonstrated that by preparing an oil-in-water emulsion composition containing human ceramide, which has a short-term healing effect on the symptoms of xerosis in addition to the moisturizing effect of a heparinoid, as described above, it is possible to provide an external skin application that can exhibit a high short-term healing effect on the symptoms of xerosis while eliminating the drawbacks of water-in-oil creams.

[0014] The present invention has found that by incorporating a heparinoid and N-stearoyldihydrosphingosine into an oil-in-water emulsion composition and applying the composition to the skin, a high moisturizing effect is exhibited, while at the same time protecting the trunk from dryness and exhibiting an excellent barrier function repair effect. That is, as a specific embodiment, the present invention provides an oil-in-water emulsion composition containing a heparinoid and N-stearoyldihydrosphingosine, and an external skin application agent for the treatment of xerosis, which contains the oil-in-water emulsion composition.

[0015] In the present invention, the term "heparinoid" refers to a substance having a similar structure or action to "heparin" which has a blood coagulation inhibitory effect, and is physically called polysulfated chondroitin sulfate. In the present invention, in particular, mucopolysaccharide polysulfate esters that meet the criteria for "heparinoids" listed in the Japanese Pharmacopoeia can be used.

[0016] Heparinoids have hydrophilicity and water retention properties, and have a very high moisturizing effect, as well as a blood circulation promoting effect and an anti-inflammatory effect. In the oil-in-water emulsion composition of the present invention, heparinoids can be added as essential components to utilize such functions as a high moisturizing effect, a blood circulation promoting effect, and an anti-inflammatory effect in order to improve the pathological condition of the skin of patients with xerosis.

[0017] The human ceramide used as one of the components of the present invention is one of the components constituting the intercellular lipids found in the stratum corneum of human skin, and in terms of chemical structure, refers to a structure in which a sphingoid base is used as the backbone and a saturated fatty acid or a monounsaturated fatty acid is amide-bonded to the amino group (-NH2) of the sphingoid base. It is known that such ceramides mainly exist in 12 types of components due to the combination of the sphingoid base and fatty acid as shown below (Non-Patent Document 1). Representative ceramides are shown in Table 1 below. In this table, the notation "ceramide + number" in the lower part of each column is the old name, and has been revised to the revised name "ceramide + alphabet" in the upper part of each column in accordance with academic fields such as dermatology.

[0018] [Table 1]

[0019] Here, the fatty acid is N: Non-hydroxy FA A: Alpha hydroxy FA EO: Ester-linked Omega hydroxy FA are shown respectively.

[0020] In addition, as a sphingoid base, DS: Dihydrosphingosine S: Sphingosine P: Phytosphingosine H: 6-Hydroxysphingosine are shown respectively.

[0021] Ceramides in the human stratum corneum play a physicochemical role in determining the barrier against cell permeability and water retention function in the skin, and are also considered to play a physiological role in signal transduction and cell regulation related to apoptosis, cell proliferation arrest, differentiation, aging, and immune response, as well as a physicochemical role as a matrix for membrane protein binding. In the oil-in-water emulsion composition of the present invention, ceramides can also be added as essential components to utilize functions such as the barrier function that protects the skin from external stimuli and the water retention function in order to improve the pathological condition of the skin of patients with xerosis.

[0022] These ceramides are known to exist in the body (within the stratum corneum) in a free state in the ratios shown in Table 2 below (Non-Patent Document 2).

[0023] [Table 2]

[0024] The human ceramide used in the present invention may be any of the above-mentioned human ceramides, and may be selected based on criteria such as ceramides frequently present in the body, ceramides that are decreased in the skin of patients with xerosis, etc. In the present invention, any one of these ceramides may be used as the human ceramide, or any two or more of these may be used in combination.

[0025] In the present invention, for example, N-stearoyldihydrosphingosine, which is a component classified as ceramide NDS (ceramide 10) (formerly known as ceramide NG and ceramide 2), may be used. N-stearoyldihydrosphingosine is a substance that has been shown to improve the barrier and enhance water retention by reinforcing ceramide when applied to a rough skin model caused by surfactant treatment on the inside of the forearm.

[0026] The present invention provides an oil-in-water emulsion composition containing the above-mentioned heparinoid and human ceramide. Here, the oil-in-water emulsion composition is a composition (emulsion, emulsion) in which oil is dispersed and emulsified in an aqueous solution. In order to reduce the oily feeling during use, the oil-in-water emulsion composition of the present invention may contain 10 to 40% by weight of an oily component, more preferably 15 to 35% by weight, and even more preferably 20 to 30% by weight, based on the total weight of the oil-in-water emulsion composition.

[0027] In the present invention, the oil-in-water emulsion composition can be prepared by stirring an oil phase having a desired composition and an aqueous phase having a desired composition while heating them to 70 to 80°C, stirring the oil phase at 4000 to 8000 rpm (approximately 6000 rpm) and gradually adding the aqueous phase while stirring to emulsify, and then cooling with further stirring to produce an emulsion composition (cream).

[0028] The oil-in-water emulsion composition of the present invention may contain a heparinoid in an amount of 0.01 to 1 mass %, preferably 0.1 to 0.5 mass %, and more preferably 0.1 to 0.3 mass %, based on the total weight of the oil-in-water emulsion composition.

[0029] Furthermore, the oil-in-water emulsion composition of the present invention may contain 0.01 to 5 mass %, preferably 0.1 to 1 mass %, and more preferably 0.2 to 0.5 mass % of N-stearoyldihydrosphingosine based on the total weight of the oil-in-water emulsion composition.

[0030] The present invention also found that by further containing hydrogenated soybean phospholipid in addition to heparinoid and N-stearoyldihydrosphingosine in the oil-in-water emulsion composition, the affected area is protected from drying and an excellent barrier function repair effect is exhibited. That is, as a specific further aspect, the present invention provides an oil-in-water emulsion composition containing heparinoid, N-stearoyldihydrosphingosine and hydrogenated soybean phospholipid, and an external skin application agent for the treatment of xerosis, which contains the oil-in-water emulsion composition.

[0031] The hydrogenated soybean phospholipid used as one of the additional components of the present invention is a substance that is also called hydrogenated soybean lecithin because it is a hydrogenated soybean phospholipid. The hydrogenated soybean lecithin is characterized by a significantly increased proportion of phosphatidylcholine in the phospholipid composition and a high emulsifying power compared to soybean lecithin. Therefore, hydrogenated lecithin is a substance that is expected to have a synergistic effect with heparinoids because it has high skin affinity and moisturizing effect. In addition, as for the fatty acid composition, the proportion of unsaturated fatty acids such as linoleic acid and oleic acid is significantly reduced compared to soybean lecithin, while the proportion of stearic acid, a saturated fatty acid, is significantly increased, so it is characterized by a very high stability against heat and oxidation compared to soybean lecithin.

[0032] The oil-in-water emulsion composition of the present invention may contain 0.01 to 5 mass %, preferably 0.1 to 1 mass %, and more preferably 0.2 to 0.5 mass %, of hydrogenated soybean phospholipid based on the total weight of the oil-in-water emulsion composition.

[0033] In addition, the present invention has shown that components known to be used in combination with heparinoids as general medicines may be added, and that in such cases, excellent moisturizing and protective effects are also exhibited. That is, when an oil-in-water emulsion composition containing a heparinoid and N-stearoyldihydrosphingosine is further combined with panthenol, tocopherol acetate, and / or dipotassium glycyrrhizinate, or when an oil-in-water emulsion composition containing a heparinoid, N-stearoyldihydrosphingosine, and hydrogenated soybean phospholipid is further combined with panthenol, tocopherol acetate, and / or dipotassium glycyrrhizinate, excellent moisturizing and protective effects are exhibited, and the drug is found to have a healing effect on xerosis in a short period of time. That is, the present invention has, as a specific further embodiment, an oil-in-water emulsion composition containing a heparinoid and N-stearoyldihydrosphingosine, and further containing one to three components selected from the group consisting of panthenol, tocopherol acetate, and dipotassium glycyrrhizinate; or An oil-in-water emulsion composition containing a heparinoid, N-stearoyldihydrosphingosine, and a hydrogenated soybean phospholipid, and further containing one to three components selected from the group consisting of panthenol, tocopherol acetate, and dipotassium glycyrrhizinate; and A skin topical application agent for treating xeroderma, comprising any one of these oil-in-water emulsion compositions. to provide.

[0034] Panthenol, which is used as one of the additional components of the present invention, is a water-soluble provitamin also called provitamin B5, which is converted into vitamin B5 (pantothenic acid) in the body, and has skin tissue repairing action, anti-inflammatory effect, moisturizing action, etc. Because of such effects, it is blended in cosmetics such as lotions and creams for the purpose of improving rough skin caused by dryness, etc. It can also be added to the oil-in-water emulsion composition of the present invention to utilize such functions as skin tissue repairing action, anti-inflammatory effect, moisturizing action, etc., in order to improve the pathology of the skin of patients with xerosis.

[0035] The oil-in-water emulsion composition of the present invention may contain panthenol in an amount of 0.1 to 10% by mass, preferably 1 to 10% by mass, and more preferably 1 to 5% by mass, based on the total weight of the oil-in-water emulsion composition.

[0036] Tocopherol acetate used as one of the additional components of the present invention is a vitamin E derivative in which the hydroxy group (-OH) at the 6-position of tocopherol is esterified with acetic acid, and when it penetrates the skin, it is converted to tocopherol by esterase present in the epidermis, and is a component that can exert antioxidant and blood circulation promoting effects as tocopherol in the skin. It can also be added to the oil-in-water emulsion composition of the present invention to utilize such functions as antioxidant and blood circulation promoting effects in order to improve the pathological condition of the skin of patients with xerosis.

[0037] The oil-in-water emulsion composition of the present invention may contain 0.001 to 5.0 mass %, preferably 0.05 to 3.0 mass %, and more preferably 0.1 to 2.0 mass %, of tocopherol acetate based on the total weight of the oil-in-water emulsion composition.

[0038] Dipotassium glycyrrhizinate, which is used as one of the additional components of the present invention, is a component that can exert an anti-inflammatory effect by suppressing prostaglandin E2 production, an anti-allergic effect by inhibiting hyaluronidase activity, and an effect of mitigating skin irritation. It can also be added to the oil-in-water emulsion composition of the present invention to utilize such functions as an anti-inflammatory effect, an anti-allergic effect, and an effect of mitigating skin irritation.

[0039] The oil-in-water emulsion composition of the present invention may contain dipotassium glycyrrhizinate in an amount of 0.01 to 2 mass %, preferably 0.1 to 2 mass %, and more preferably 0.1 to 1 mass %, based on the total weight of the oil-in-water emulsion composition.

[0040] In the treatment of xerosis, moisturizing is basically important, but if the affected area is itchy or red, it is in a state of inflammation in addition to dryness, and it is necessary to first use a topical steroid to suppress the inflammation that causes itching and redness, and then moisturize. In addition, when the itching is severe, it is also necessary to take an oral antiallergic drug. Since the oil-in-water emulsion composition of the present invention contains ingredients that have an anti-inflammatory effect, it is possible to avoid or reduce the application of topical steroids and antiallergic drugs to patients with inflammation. In addition, unlike the application of ingredients using topical agents using conventional water-in-oil creams, it has a less oily feel and is excellent in usability, so there is no need to wipe off after application, and a sufficient amount of the drug can be rubbed into the affected area and penetrated, so a higher therapeutic effect can be expected.

[0041] The present invention will be described in more detail below with reference to examples, but the following examples are not intended to limit the present invention in any way. EXAMPLES

[0042] Example 1: Preparation of test formulations In this example, a test formulation was prepared for use in the present invention.

[0043] For each of the Preparation Examples and Comparative Examples shown in Table 3, the oil phase and the water phase containing the indicated composition were dissolved by stirring at 70 to 80°C.

[0044] The aqueous phase was gradually added to the oil phase while stirring to pre-emulsify, and then the mixture was emulsified at approximately 6000 rpm using a homogenizer (Omni Homogenizer GLH, Yamato Scientific Co., Ltd.) to obtain each formulation. The emulsion composition (cream) was obtained by cooling the mixture while stirring.

[0045] [Table 3]

[0046] Example 2: Study of the desired oil-in-water cream In this example, the effects of the various creams prepared in Example 1 were compared in order to identify the composition of the oil-in-water cream of the present invention.

[0047] A circular mark measuring 2 cm in diameter was made on the skin of the inner forearm of human subjects (male and female, ages 20s to 30s) to serve as the measurement site.

[0048] To prepare a rough skin model, cellophane tape (Cellotape (registered trademark), Nichiban Co., Ltd.) was applied to the measurement site and then peeled off seven times.

[0049] (2-1) Measurement of stratum corneum moisture content and transepidermal water loss After the treatment, the test cream was applied to the measurement site, and the stratum corneum moisture content and transepidermal water loss were measured one hour after application. Measurements of stratum corneum moisture content and transepidermal water loss were performed using a measuring device (MDD4, Courage+Khazaka) connected to a measuring probe (stratum corneum moisture content: Corneometer CM 825) and transepidermal water loss: Tewameter TM 300).

[0050] The results of measuring the moisture content of the stratum corneum one hour after application of each cream are shown in Figure 1, and the results of measuring the transepidermal water loss are shown in Figure 2. The untreated group, to which no cream was applied, was used as the "control." The values ​​on the graph show the average value of six cases in each group, and the error bars show the standard error.

[0051] A higher moisture content in the stratum corneum indicates a moisturized state of the skin, whereas a lower moisture content indicates dryness. In this experiment, the moisture content in the stratum corneum was significantly increased by application of all creams, including the comparative example.

[0052] The transepidermal water loss indicates the amount of water lost from the skin, and is low when the skin barrier function is high and high when the skin barrier function is low. In contrast to the measurement results of the stratum corneum moisture content, the transepidermal water loss was lower in Preparation Examples 1 and 2 than in Comparative Example 1, and a water loss suppression effect equal to or greater than that of Comparative Example 2 was observed.

[0053] (2-2) Measurement of stratum corneum moisture content and transepidermal water loss after washing and drying the measurement area Furthermore, 3 hours after application of the cream, paper soaked in a 3% aqueous solution of sodium lauryl sulfate was pressed against the measurement site for a few seconds and then washed with tap water.

[0054] After that, purified water was poured over the area, the moisture was wiped off with paper, and the area was allowed to dry for at least 15 minutes, after which the stratum corneum moisture content and transepidermal water loss were measured in the same manner. The measurement results for stratum corneum moisture content after washing and drying of the measurement area are shown in Figure 3, and the measurement results for transepidermal water loss are shown in Figure 4.

[0055] As a result of comparing the moisture content of the stratum corneum, in Comparative Example 2, it decreased to the same level as the control, but maintained a higher value than the control in Comparative Example 1, Preparation Examples 1, and 2. On the other hand, the transepidermal water loss was decreased in Preparation Examples 1 and 2 compared to Comparative Example 1, and the tendency before washing was maintained.

[0056] (2-3) Discussion When creams etc. are applied to the skin, in the short term, the oil in the formulation covers the skin surface and inhibits water evaporation, which is thought to reduce transepidermal water loss. In the long term, the cream etc. is effective in restoring the skin barrier function, which is thought to reduce transepidermal water loss to normal levels.

[0057] The results of this example showed that the combination of a heparinoid and N-stearoyldihydrosphingosine (Preparation Example 1), and the combination of the added hydrogenated soybean phospholipid (Preparation Example 2) showed a transepidermal water loss inhibitory effect equal to or greater than that of a water-in-oil cream, despite being oil-in-water creams.

[0058] The continuous phase of the water-in-oil cream is an oil phase, and it is believed that the transepidermal water loss is reduced by forming an oil film on the skin surface. However, after washing the application site, the stratum corneum moisture content of the water-in-oil cream (Comparative Example 2) decreased to the same level as the control. On the other hand, the oil-in-water cream (Preparation Example 1 or Preparation Example 2) showed that the stratum corneum moisture content remained relatively high even after washing.

[0059] This means that although the water-in-oil cream has an excellent effect of covering and protecting the skin surface, the moisturizing ingredients such as heparinoids hardly penetrate into the stratum corneum and are washed away with the preparation during washing. From this, it was considered that the oil-in-water cream (Preparation Example 1 or Preparation Example 2) is more advantageous for allowing moisturizing ingredients such as heparinoids to penetrate into the stratum corneum and moisturize the skin.

[0060] Example 3: Investigation of further active ingredients In this example, an experiment was conducted to investigate active ingredients that can be further added to the preparation examples containing the active ingredients selected in Example 2.

[0061] Specifically, we investigated whether similar effects could be obtained when an oil-in-water cream containing heparinoids, N-stearoyldihydrosphingosine, and hydrogenated soybean phospholipids (Preparation Example 2) was further formulated with medicinal ingredients such as panthenol, tocopherol acetate, and dipotassium glycyrrhizinate (Preparation Example 3).

[0062] The transepidermal water loss was measured 1 hour after application of the cream. The control group was not treated with the cream.

[0063] The results are shown in Figure 5. Each value in this graph indicates the average value of three cases in each group, and the error bars indicate the standard error.

[0064] In comparison with Preparation Example 2, Preparation Example 3 increased the moisture content of the stratum corneum to the same extent while simultaneously suppressing the amount of transepidermal water loss.

[0065] This indicates that the transepidermal water loss inhibitory effect of the combination of heparinoids, N-stearoyldihydrosphingosine and hydrogenated soybean phospholipid (Preparation Example 2) is also exerted when panthenol, tocopherol acetate and / or dipotassium glycyrrhizinate are added as other active ingredients.

[0066] Example 4: Study of essential components of the cream of the present invention In this Example, in order to confirm that the inhibitory effect of the cream of the present invention on transepidermal water loss observed in Examples 2 and 3 is not the sole effect of N-stearoyldihydrosphingosine or hydrogenated soybean phospholipid, the effects were compared and verified with those of Comparative Example 3 and Comparative Example 4.

[0067] The measurement was performed 1 hour after application of the cream. The non-treatment group without application of the cream was used as the "control". Other basic experimental protocols were performed in the same manner as in Example 2 or Example 3.

[0068] The results are shown in Figure 6. Each value in this graph indicates the average value of three cases in each group, and the error bars indicate the standard error.

[0069] Compared to Comparative Example 1, the effects of Comparative Example 3 (preparation not containing heparinoids or hydrogenated soybean phospholipids) and Comparative Example 4 (preparation not containing heparinoids or N-stearoyldihydrosphingosine) in reducing transepidermal water loss were equal to or less than that of Comparative Example 1.

[0070] The results of this example showed that N-stearoyldihydrosphingosine and hydrogenated soybean phospholipid alone did not have a high inhibitory effect on transepidermal water loss, but that this effect was due to the combination with a heparinoid.

[0071] Example 5: Effect of continuous application of the cream of the present invention The purpose of this example was to examine the effect of continuously applying the cream of the present invention on improving dry skin in subjects.

[0072] The skin of four locations on the back of the hand (near the center of the metacarpal bones of the thumb, index finger, middle finger, and little finger) of a human subject (a man in his 30s who was concerned about dry hands) was used as the measurement site. The cream of Comparative Example 2 or Preparation Example 3 was applied to the back of the right or left hand three times a day (morning, noon, and night) for 10 days.

[0073] For these subjects, the stratum corneum moisture content and transepidermal water loss were measured on the first day of application, the day after application began, and on the second, third, fourth, seventh, and tenth days. Measurements were taken in the morning before application of the cream.

[0074] The stratum corneum moisture content and transepidermal water loss were measured using the same measuring device and measuring probe as in Example 2.

[0075] The measurement results of the stratum corneum moisture content are shown in Figure 9, and the measurement results of the transepidermal water loss are shown in Figure 10. The values ​​in the graph show the average values ​​of four locations, and the error bars show the standard error.

[0076] In Comparative Example 2, it took 7 to 10 days for the stratum corneum moisture content to improve, whereas it reached its maximum value after 3 days in Preparation Example 3. On the other hand, the transepidermal water loss was suppressed in 7 to 10 days in both Comparative Example 2 and Preparation Example 3.

[0077] The results of this example showed that the oil-in-water cream of the present invention showed a tendency for improvement in about 3 days compared to the water-in-oil cream containing a heparinoid, and could significantly shorten the time until the effect was exerted.

[0078] Example 6: Effect of application of the cream of the present invention (histological images) In this example, the changes over time in skin tissue after application of the oil-in-water emulsion composition of the present invention were examined.

[0079] The skin on the back of the hand of a human subject (a man in his 30s who was concerned about dry hands) was applied at four locations (near the center of the metacarpal bones of the thumb, index finger, middle finger, and little finger). The cream was applied three times a day (morning, noon, and night) to the back of the right or left hand for seven days.

[0080] At the start of application of the oil-in-water emulsion composition of the present invention (day 0) and on day 7, the stratum corneum was sampled by pressing an adhesive tape for stratum corneum diagnosis (Keratin Checker AST-01, Nippon Ash Co., Ltd.) against the skin on the back of the hand of the human subject. These were immersed in a staining solution (a solution prepared by dissolving 0.5 g of brilliant green and 1 g of gentian violet in 25 mL of ethanol and adding 75 mL of water to the solution) for 20 minutes, after which the staining solution was washed off with water and the sample was immersed in water for another 20 minutes, sealed in glycerin, and observed under a microscope.

[0081] The results are shown in Figure 9-1. The large blue lumps are dried desquamation of the skin. At the site where Preparation Example 3 was applied, desquamation was hardly observed by the 7th day. On the other hand, at the site where Comparative Example 2 was applied, although there was an improvement from the start, desquamation still remained.

[0082] For comparison, the stratum corneum of a healthy subject whose skin did not feel dry was also observed in the same way, and no disruption of the stratum corneum (large blue lumps) was found (Figure 9-2).

[0083] The change over time in the appearance of the skin of subjects when the oil-in-water emulsion composition of the present invention was applied to these tissues is shown in Figure 10. At the start (day 0), dry roughness (white peeling scales) was observed at the application sites of both Comparative Example 2 and Preparation Example 3. Furthermore, by the seventh day, the roughness had improved to the point where it was no longer noticeable to the naked eye in both Comparative Example 2 and Preparation Example 3. Meanwhile, by the third day, the roughness had improved in Preparation Example 3, whereas scales were still visually observed in Comparative Example 2.

[0084] As described above, the effect of Preparation Example 3 was visually observable on the third day, demonstrating that the subjects were able to feel the effect. [Industrial Applicability]

[0085] The present invention provides an oil-in-water emulsion composition containing human ceramide, which has a short-term healing effect on the symptoms of xerosis in addition to the moisturizing effect of a heparinoid, thereby providing an external skin application agent that can exert a high short-term healing effect on the symptoms of xerosis while eliminating the drawbacks of water-in-oil creams.

Claims

1. An oil-in-water emulsion composition comprising a heparinoid and N-stearoyldihydrosphingosine.

2. 2. The composition for external application to skin according to claim 1, wherein the content of the heparinoid is 0.1 to 0.5% by mass, and the content of N-stearoyldihydrosphingosine is 0.1 to 1% by mass.

3. 3. The skin external application preparation according to claim 1, further comprising one to three components selected from the group consisting of panthenol, tocopherol acetate, and dipotassium glycyrrhizinate.

4. 4. The skin external application preparation according to claim 3, wherein the panthenol content is 1 to 10% by mass, the tocopherol acetate content is 0.05 to 3.0% by mass, and the dipotassium glycyrrhizinate content is 0.1 to 2% by mass.

5. An oil-in-water emulsion composition comprising a heparinoid, N-stearoyldihydrosphingosine and hydrogenated soybean phospholipid.

6. 6. The composition for external application to skin according to claim 5, wherein the content of the heparinoid is 0.1 to 0.5% by mass, the content of the N-stearoyldihydrosphingosine is 0.1 to 1% by mass, and the content of the hydrogenated soybean phospholipid is 0.1 to 1% by mass.

7. 7. The skin external application preparation according to claim 5 or 6, further comprising one to three components selected from the group consisting of panthenol, tocopherol acetate, and dipotassium glycyrrhizinate.

8. 8. The skin topical application preparation according to claim 7, wherein the panthenol content is 1 to 10% by mass, the tocopherol acetate content is 0.05 to 3.0% by mass, and the dipotassium glycyrrhizinate content is 0.1 to 2% by mass.

9. An external skin application preparation for treating xerosis, comprising an oil-in-water emulsion composition containing a heparinoid and N-stearoyldihydrosphingosine, or an oil-in-water emulsion composition containing a heparinoid, N-stearoyldihydrosphingosine, and hydrogenated soybean phospholipid.

10. 10. The skin topical application preparation according to claim 9, wherein the heparinoid content is 0.1 to 0.5% by mass, the N-stearoyldihydrosphingosine content is 0.1 to 1% by mass, and the hydrogenated soybean phospholipid content is 0.1 to 1% by mass.

11. The skin external application preparation according to claim 9 or 10, further comprising one to three components selected from the group consisting of panthenol, tocopherol acetate, and dipotassium glycyrrhizinate.

12. The skin external application preparation according to claim 11, wherein the panthenol content is 1 to 10% by mass, the tocopherol acetate content is 0.05 to 3.0% by mass, and the dipotassium glycyrrhizinate content is 0.1 to 2% by mass.

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