JP2025028638A - A topical application agent that is a water-in-oil emulsion composition for treating dry skin - Google Patents

Abstract

To provide a water-in-oil emulsion composition with superior moisturizing and protective effects, designed for alleviating and treating symptoms of xerosis, to provide a topical skin application agent exhibiting a high therapeutic effect in a short period, and to address an issue of thermodynamic instability in water-in-oil emulsion compositions, which makes them prone to water separation during storage.SOLUTION: The present invention provides a water-in-oil emulsion composition containing a heparinoid and ceramide. Preferably, the ceramide is N-stearoyl dihydrosphingosine. Further, incorporation of (1) octyldodecanol or (2) a combination of triglycerides and N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide results in a stable water-in-oil emulsion composition, preventing water separation.SELECTED DRAWING: None

Description

The present invention relates to a topical skin application agent that uses a heparinoid, and in particular to a topical skin application agent that is highly effective in treating xeroderma.

Heparinoids are a type of polysaccharide that have many hydrophilic groups such as sulfate, hydroxyl, and carboxyl groups in their molecular structure, and are widely used in the treatment of dry skin diseases such as xerosis due to their excellent moisturizing effect. In particular, they are often used as water-in-oil creams for the purpose of protecting the affected area while also providing moisturizing effects. Since the continuous phase in the emulsion composition of water-in-oil creams is the oil phase, they are thought to be highly effective in suppressing water evaporation and protecting the affected area from dryness.

However, in reality, the moisturizing effect weakens within a few hours of application, meaning that frequent reapplication is required to maintain the effect. Another issue is that it takes a long time for the moisturizing effect of heparinoids to improve the symptoms of xerosis.

Human ceramide, which is used as a component to provide functions such as a barrier function to protect the skin from external stimuli and a moisture-retaining function, is one of the components that constitute the intercellular lipids found in the stratum corneum of human skin, and is a compound that has a sphingoid base as a backbone and has a saturated or monounsaturated fatty acid bonded to its amino group ( _-NH2 ) via an amide bond. It is known that there are 12 types of ceramides, mainly depending on the combination of the sphingoid base and the fatty acid (Non-Patent Document 1).

Ceramides in the human stratum corneum are thought to play a physicochemical role in determining the barrier against cell permeability and water retention in the skin, as well as a physicochemical role as a matrix for membrane protein binding, and also a physiological role in signal transduction and cell regulation related to apoptosis, cell growth arrest, differentiation, aging, and immune response.

Masukawa, Y., et al., J. Lipid Res. 2008. 49: 1466-1476 Robson, K.J., et al., J. Lipid Res. 1994. 35: 2060-2068

The present invention aims to provide a water-in-oil emulsion composition with excellent moisturizing and protective effects for improving and curing the symptoms of xerosis, and further to provide a skin topical application that can exert a high curative effect in a short period of time. Another object of the present invention is to solve the problem that water-in-oil emulsion compositions are thermodynamically unstable and tend to synerase during storage.

According to the present invention, it has been found that by incorporating a heparinoid and ceramide, more specifically a heparinoid and N-stearoyldihydrosphingosine, into a water-in-oil emulsion composition and applying the composition to the skin, a high moisturizing effect continues to be exerted for a long period of time. Furthermore, it has also been found that by applying the above water-in-oil emulsion composition to dry skin, a healing effect is exerted in a short period of time. Furthermore, it has been found that by blending a combination of (1) octyldodecanol or (2) triglyceride and N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide to dissolve N-stearoyldihydrosphingosine, syneresis can be prevented and a stable water-in-oil emulsion composition can be obtained.

More specifically, in order to solve the above-mentioned problems, the present application provides the following aspects:
[1]: A water-in-oil emulsion composition containing a heparinoid and a ceramide;
[2]: the water-in-oil emulsion composition according to [1], wherein the ceramide is N-stearoyldihydrosphingosine;
[3]: the water-in-oil emulsion composition according to [1] or [2], wherein the heparinoid content is 0.1 to 0.5% by mass and the N-stearoyldihydrosphingosine content is 0.1 to 1% by mass;
[4] In addition, any of the following ingredients:
(1) Octyldodecanol,
(2) triglyceride and N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide,
The water-in-oil emulsion composition according to claim 1 or 2,
[5]: (1) The water-in-oil emulsion composition according to [4], containing 3.0% by mass or less of octyldodecanol;
[6]: The water-in-oil emulsion composition according to [4], wherein the triglyceride in (2) is selected from the group consisting of glyceryl tri-2-ethylhexanoate, caprylic/capric triglyceride, and medium-chain triglyceride;
[7]: The water-in-oil emulsion composition according to [4], wherein the amount of N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide in (2) is 1.3 times or more by mass relative to the amount of ceramide;
[8]: Any of the following ingredients:
(1) Octyldodecanol,
(2) triglyceride and N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide,
A stabilizer for a water-in-oil emulsion composition containing a heparinoid and a ceramide, comprising:
[9]: the stabilizer for a water-in-oil emulsion composition according to [8], wherein the ceramide is N-stearoyldihydrosphingosine;
[10]: the stabilizer for a water-in-oil emulsion composition according to [8] or [9], wherein the heparinoid content is 0.1 to 0.5% by mass and the N-stearoyldihydrosphingosine content is 0.1 to 1% by mass;
[11]: (1) The stabilizer for the water-in-oil emulsion composition according to [8] or [9], which contains 3.0% by mass or less of octyldodecanol;
[12]: The stabilizer for a water-in-oil emulsion composition according to [8] or [9], wherein the triglyceride in (2) is selected from the group consisting of glyceryl tri-2-ethylhexanoate, glyceryl tri(caprylate/caprate), and medium-chain triglyceride;
[13]: The stabilizer for a water-in-oil emulsion composition according to [12], wherein the amount of N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide in (2) is 1.3 times or more by mass relative to the amount of ceramide;
[14]: A water-in-oil emulsion composition containing a heparinoid and a ceramide, comprising any one of the following components:
(1) Octyldodecanol,
(2) triglyceride and N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide,
A method for stabilizing a water-in-oil emulsion composition containing a heparinoid and a ceramide by including
[15]: The method according to [14], wherein the ceramide is N-stearoyldihydrosphingosine;
[16]: The method according to [14] or [15], wherein the content of heparinoid is 0.1 to 0.5% by mass and the content of N-stearoyldihydrosphingosine is 0.1 to 1% by mass;
[17]: (1) The method according to [14] or [15], wherein octyldodecanol is contained in an amount of 3.0% by mass or less;
[18]: The method according to [14] or [15], wherein the triglyceride in (2) is selected from the group consisting of tri-2-ethylhexanoate glyceryl, tri(caprylic/capric acid)glyceryl, and medium-chain fatty acid triglycerides;
[19]: The method according to [18], wherein in (2), N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide is contained in an amount 1.3 times or more by mass relative to the ceramide.

According to the present invention, it has been found that by incorporating a heparinoid and ceramide, more specifically a heparinoid and N-stearoyldihydrosphingosine, into a water-in-oil emulsion composition and applying the composition to the skin, a high moisturizing effect continues to be exerted for a long period of time, and the water-in-oil emulsion composition can be provided. Furthermore, it has been found that by applying the water-in-oil emulsion composition to dry skin, a healing effect is exerted in a short period of time, and further, by blending a combination of (1) octyldodecanol or (2) triglyceride and N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide to dissolve N-stearoyldihydrosphingosine, syneresis can be prevented and a stable water-in-oil emulsion composition can be obtained.

FIG. 1 shows the results of applying various test preparations to the skin on the inside of the forearm of a human subject and then measuring the change in moisture content in the stratum corneum over time. FIG. 2 shows the results of applying a test preparation to the skin of the inner forearm of a human subject who was concerned about dryness, and then measuring the change in moisture content in the stratum corneum. FIG. 3 shows the results of applying a test preparation to the skin of the inner forearm of a human subject who was concerned about dryness at the same site, and observing the stratum corneum on the first day and the seventh day. FIG. 4 shows the results of observation of the stratum corneum of a healthy subject who does not feel dry skin. FIG. 5 shows the results of applying a test preparation to the skin of a subject with dry, rough skin on the upper arm, and then measuring the change in moisture content in the stratum corneum over time. FIG. 6 shows the results of applying the test preparation to the skin of a subject with dry, rough skin on the upper arm, and observing the stratum corneum on the first day and the seventh day.

The inventors of the present invention conducted intensive research to solve the above-mentioned problems, and as a result, demonstrated that by including human ceramide, which has a short-term healing effect on the symptoms of xerosis in addition to the moisturizing effect of heparinoids, as described above, when a water-in-oil emulsion composition is prepared, the problem that the water-in-oil emulsion composition is thermodynamically unstable and prone to separation of water during storage can be solved, and that the water-in-oil emulsion composition thus prepared can provide an external skin application agent that has excellent moisturizing and protective effects and can exert a high healing effect in a short period of time.

In a first aspect, the present invention can provide a water-in-oil emulsion composition containing a heparinoid and a ceramide. In the present invention, in order to disperse a heparinoid in a water-in-oil emulsion composition containing a heparinoid, it is necessary to disperse an aqueous component in which the heparinoid is dissolved in an oil phase component containing ceramide, and for this purpose, a surfactant is used as a lipophilic emulsifier.

Examples of such lipophilic emulsifiers include glycerin fatty acid esters, sorbitan monooleate, sorbitan sesquioleate, polyoxyethylene hydrogenated castor oil, etc. Examples of emulsifiers that can be used in the present invention include polyglyceryl-2 oleate, sorbitan monooleate, sorbitan sesquioleate, PEG-5 hydrogenated castor oil, etc.

Methods for producing water-in-oil creams are well known in the art, for example, a method in which water is added while stirring the oil phase, but they may also be produced according to other methods well known in the art (for example, the method described in the "New Cosmetics Handbook").

The heparinoid used as an ingredient in the water-in-oil emulsion composition of the present invention is a substance that has 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 Extra Pharmaceutical Standards can be used.

The heparinoid used as an ingredient in the water-in-oil emulsion composition of the present invention can be contained in an amount of 0.1 to 50 mg (0.01 to 5%), more preferably 0.5 to 10 mg (0.05 to 1%), even more preferably 1.0 to 5.0 mg (0.1 to 0.5%), and most preferably 3.0 mg (0.3%) per gram of the water-in-oil emulsion composition.

Ceramide, which is used as another component in the water-in-oil emulsion composition of the present invention, is one of the components that constitute the intercellular lipids found in the stratum corneum of human skin, and is a compound that has a sphingoid base as a backbone and has a saturated or monounsaturated fatty acid bonded to its amino group ( _-NH2 ) via an amide bond. It is known that such ceramides exist in 12 types of components, mainly due to the combination of sphingoid bases and fatty acids 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.

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

Also, as a sphingoid base,
DS: Dihydrosphingosine
S: Sphingosine
P: Phytosphingosine
H: 6-Hydroxysphingosine
are shown respectively.

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 thought 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 topical skin application 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 dermatitis.

It is known that these ceramides exist in the body (stratum corneum) in a free state in the ratios shown in Table 2 below (Non-Patent Document 2).

The ceramide used in the present invention may be any of the ceramides described above, and may be selected based on criteria such as a ceramide that is frequently present in the body, or a ceramide that is decreased in the skin of patients with dermatitis.

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.

When N-stearoyldihydrosphingosine is used as an example of a ceramide in the topical skin application preparation of the present invention, the topical skin application preparation may contain 0.1 to 50.0 mg (0.01 to 5% by mass), preferably 1.0 to 10.0 mg (0.1 to 1% by mass), and more preferably 2.0 to 5.0 mg (0.2 to 0.5% by mass) of N-stearoyldihydrosphingosine per 1 g of the topical skin application preparation.

In the present invention, octyldodecanol can be added to dissolve N-stearoyldihydrosphingosine in the oil phase, but since syneresis can occur depending on the amount added, it has been found that adding it at 3% or less is effective. In addition, it has been found that by adding N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide, N-stearoyldihydrosphingosine can be dissolved in triglyceride without adding octyldodecanol, and a stable water-in-oil emulsion composition can be obtained.

Based on this, in the present invention, when preparing a water-in-oil emulsion composition, any one of the following components is added to the oil phase:
(1) Octyldodecanol,
(2) triglyceride and N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide,
By including the above-mentioned component (I), after the production of the water-in-oil emulsion composition, syneresis is suppressed for a relatively long period of time, and the oil phase containing the ceramide can be stably present in the water-in-oil emulsion composition.

In the present invention, octyldodecanol that can be used in the oil phase is a monohydric alcohol and synthetic alcohol (higher alcohol) with a side chain structure of 20 carbon atoms, and is a substance used in external preparations for the purpose of base, emulsification, solvent, and dissolution aid. Octyldodecanol is widely used as an oil base because it gives a refreshing feeling without stickiness and has excellent stability over time. In the present invention, unlike the previously known action, it can be used as a stabilizer for preparing a stable water-in-oil emulsion composition in a water-in-oil emulsion composition. As a result, when octyldodecanol is used in a water-in-oil emulsion composition, more specifically, a stable water-in-oil emulsion composition can be prepared by dissolving octyldodecanol in 3 mass% or less to prepare the oil phase.

In the present invention, a combination of triglyceride and N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide can be used in the oil phase to prepare a stable water-in-oil emulsion composition.

Triglycerides are substances in which three fatty acids are bound to glycerin, and are generally used as emulsifiers and oily bases in cosmetics, foods, etc. In the present invention, unlike such conventionally known actions, they can be used in combination with N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide, which will be described later, in a water-in-oil emulsion composition as a stabilizer for preparing a stable water-in-oil emulsion composition. In the water-in-oil emulsion composition of the present invention, triglycerides that can be used include tri-2-ethylhexanoate glyceryl, tri(caprylic/capric acid) glyceryl, and medium-chain fatty acid triglycerides.

N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide is a ceramide analogue with a structure similar to that of ceramide NS, and is also known as cetyl PG hydroxyethyl palmitamide. N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide is generally used in cosmetics to restore barrier function by regenerating lamellar liquid crystal structure. In the present invention, rather than having such a conventionally known function, it can be used in combination with triglycerides in a water-in-oil emulsion composition as a stabilizer for preparing a stable water-in-oil emulsion composition.

In the water-in-oil emulsion composition of the present invention, it is preferable that the amount of N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide is 1.3 times or more by mass relative to the amount of ceramide (e.g., N-stearoyldihydrosphingosine) contained in the oil phase component.

In a second aspect, the present invention provides a composition comprising any one of the following components:
(1) Octyldodecanol,
(2) triglyceride and N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide,
In one embodiment, a stabilizer for a water-in-oil emulsion composition containing a heparinoid and a ceramide (eg, N-stearoyldihydrosphingosine) can be provided, comprising:

As described above, unlike the previously known action of octyldodecanol, it has been shown that octyldodecanol can be used in a water-in-oil emulsion composition as a stabilizer for preparing a stable water-in-oil emulsion composition. It has also been shown that, unlike the previously known action of triglyceride and N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide, in combination, can be used in a water-in-oil emulsion composition as a stabilizer for preparing a stable water-in-oil emulsion composition.

The dosages of the various components in this embodiment of the invention (octyldodecanol, triglycerides (glyceryl tri-2-ethylhexanoate, tri(caprylic/capric)glyceride, medium chain triglycerides, etc.), N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide, heparinoids, ceramide, N-stearoyldihydrosphingosine, etc.) are as described above.

In a third aspect, the present invention provides a water-in-oil emulsion composition containing a heparinoid and a ceramide, comprising any one of the following components:
(1) Octyldodecanol,
(2) triglyceride and N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide,
It is possible to provide a method of stabilizing a water-in-oil emulsion composition containing a heparinoid and a ceramide (eg, N-stearoyldihydrosphingosine) by including

The present invention will be specifically illustrated below with reference to examples. The examples shown below are not intended to limit the present invention in any way.

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

For each of the preparation examples and comparative examples shown in Tables 3 and 4, test formulations were prepared according to the following procedure. First, oil phase component A was dissolved by stirring at 75-85°C. Oil phase component B was added to this and dissolved by stirring at 75-85°C, and oil phase component C was then added and mixed to form the oil phase. Separate from the oil phase, water phase component D was dissolved by stirring at 75-85°C.

The aqueous phase was gradually added to the oil phase with stirring to pre-emulsify, and then emulsified by stirring at approximately 6,000 rpm using a homogenizer (Omni Homogenizer GLH, Yamato Scientific Co., Ltd.).
The mixture was cooled with stirring to obtain a water-in-oil emulsion composition.

In Comparative Example 3, in which 5% by mass of octyldodecanol was blended, syneresis was observed 7 days after preparation of the water-in-oil emulsion composition, and in Comparative Example 4, in which 10% by mass of octyldodecanol was blended, syneresis was observed the day after preparation of the water-in-oil emulsion composition (see Table 3). On the other hand, in Preparation Example 1, in which 3% by mass of octyldodecanol was blended, syneresis was not observed (see Table 3). From the above, it was shown that a stable water-in-oil emulsion composition can be prepared by dissolving N-stearoyldihydrosphingosine in 3% by mass or less of octyldodecanol to prepare the oil phase.

In Comparative Examples 5, 6, and 7, N-stearoyldihydrosphingosine could not be dissolved in glyceryl tri-2-ethylhexanoate, which is a type of triglyceride, but in Preparation Examples 2, 3, and 4, N-stearoyldihydrosphingosine could be dissolved in glyceryl tri-2-ethylhexanoate (see Table 4). This is the effect of adding N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide, and indicates that the addition of 0.4 mass% or more of N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide to 0.3 mass% of N-stearoyldihydrosphingosine is effective. Furthermore, as in Preparation Example 5, when tri(caprylic/capric)glyceryl, a type of triglyceride, was used instead of glyceryl 2-ethylhexanoate, N-stearoyldihydrosphingosine was dissolved and a water-in-oil emulsion composition could be prepared (see Table 4).

Example 2: Duration of moisturizing effect of test preparations In this example, an experiment was carried out to confirm the duration of the moisturizing effect of the various test preparations prepared in Example 1.

A circular mark measuring 2 cm in diameter was made on the skin of the inside of the forearm of a human subject (male, aged 20s-30s) as the measurement site. The moisture content of the stratum corneum was measured by connecting a measurement probe (for measuring moisture content of the stratum corneum: Corneometer CM 825) to a measurement device (MDD4, Courage+Khazaka) and placing the measurement probe on the measurement site. A higher moisture content of the stratum corneum indicates a moisturized state of the skin, and a lower value indicates a drier state.

After measuring the moisture content of the stratum corneum at the measurement site, various test preparations were applied, and the moisture content of the stratum corneum was measured 1 hour, 2 hours, 3 hours, and 4 hours later. The results are shown in Figure 1. The results are the average value for n = 3 cases, and the error bars indicate the standard error.

When Comparative Example 1, Comparative Example 2, Preparation Example 1, and Preparation Example 4 were applied, the moisture content of the stratum corneum after 1 hour all increased significantly. In Comparative Example 1 and Comparative Example 2, a decrease in the moisture content of the stratum corneum was observed after 2 hours, but in Preparation Examples 1 and 4, the moisture content remained high even after 2 hours. In the control (untreated) group where no formulation was applied, the moisture content of the stratum corneum did not change.

These results indicate that the moisturizing effect is more sustained when heparinoids and N-stearoyldihydrosphingosine are used in combination rather than when used alone.

Example 3: Duration of moisturizing effect of test preparations In this example, an experiment was conducted to confirm the duration of the moisturizing effect of the various test preparations prepared in Example 1, and the condition of the stratum corneum of the skin was also confirmed.

The application site was the skin on the back of the hand of a human subject (a man in his 30s who was concerned about dry hands). The moisture content of the stratum corneum was measured by connecting a measurement probe (for measuring moisture content of the stratum corneum: Corneometer CM 825) to a measurement device (MDD4, Courage+Khazaka) and placing the measurement probe against the application site.

The effect of improving dry skin was investigated by continuously applying the water-in-oil emulsion composition of the present invention to subjects who were actually concerned about dry hands. Specifically, the drug was applied to the application site twice a day (morning and evening) for seven days. The moisture content of the stratum corneum was measured on the first day of application, the day after application began, and on the second, fourth, fifth, and seventh days. The results are shown in Figure 2. The results are the average value of four locations (n=4) within the application site, and the error bars indicate the standard error.

In Preparation Example 1, a water-in-oil emulsion composition containing both heparinoids and N-stearoyldihydrosphingosine, the moisture content of the stratum corneum increased significantly from the day after application began, reaching a maximum on the second day and maintaining a high value until the seventh day. On the other hand, in Comparative Example 1, a water-in-oil emulsion composition containing a heparinoid, the moisture content of the stratum corneum increased from the next day, but the increase was smaller than in Preparation Example 1, and it took 7 days to reach a value similar to that of Preparation Example 1.

These results suggest that the combination of heparinoids and N-stearoyldihydrosphingosine is more effective in improving dry skin symptoms in a shorter period of time than using either of them alone.

Next, on the first and seventh days, the stratum corneum was observed at the application site of the same human subjects. For observation of the stratum corneum, an adhesive tape for stratum corneum diagnosis (Keratin Checker AST-01, Nippon Ash Co., Ltd.) was pressed against the skin to sample the stratum corneum, which was then immersed in a staining solution (0.5 g of brilliant green and 1 g of gentian violet dissolved in 25 mL of ethanol, mixed with 75 mL of water) for 20 minutes, after which the staining solution was washed off with water and the sample was immersed in water for a further 20 minutes, sealed in glycerin, and observed under a microscope.

The results are shown in Figure 3. The large blue clumps are dried, peeling off keratin from the skin. Almost no desquamation was observed on the seventh day in Preparation Example 1. On the other hand, scattered desquamation was observed on the seventh day in Comparative Example 1. For comparison, the stratum corneum of a healthy subject who did not feel dry skin was also observed in the same way, and no disruption of the stratum corneum (large blue clumps) was observed (see Figure 4).

In the observation of the stratum corneum, a difference was observed between Comparative Example 1 and Preparation Example 1. This shows that even if the moisture content of the stratum corneum is approximately the same, there is a difference in the repair state of the stratum corneum.

Example 4: Duration of moisturizing effect of test preparations In this example, an experiment was conducted to confirm the duration of the moisturizing effect of the various test preparations prepared in Example 1, and the condition of the stratum corneum of the skin was also confirmed.

The application site was the skin on the outer side of the upper arm of a human subject (a man in his 30s with dry, rough upper arms). The moisture content of the stratum corneum was measured by connecting a measurement probe (stratum corneum moisture content: Corneometer CM 825) to a measurement device (MDD4, Courage+Khazaka) and placing the measurement probe against the application site.

The effect of continuously applying the water-in-oil emulsion composition of the present invention to improve dry skin was investigated on subjects who had dry, rough skin on their upper arms. Specifically, the drug was applied to the application site twice a day (morning and evening) for seven days. The moisture content of the stratum corneum was measured on the first day of application, the day after application began, and on the second, fourth, fifth, and seventh days. The results are shown in Figure 5. The results are the average value of six locations (n=6) within the application site, and the error bars indicate the standard error.

In Preparation Example 1, a water-in-oil emulsion composition containing both heparinoids and N-stearoyldihydrosphingosine, the moisture content of the stratum corneum increased significantly from the day after application began and maintained a high value until the seventh day. On the other hand, in Comparative Example 1, a water-in-oil emulsion composition containing a heparinoid, the moisture content of the stratum corneum increased from the next day, but the increase was smaller than in Preparation Example 1, and it took seven days to reach the same level as in Preparation Example 1.

From these results, although the application site (test site) was different from Example 3 and the manifestation of the effect was slightly different, the heparinoid and N-stearoyldihydrosphingosine were more effective in improving dryness symptoms in a short period of time when used in combination than when used alone.

Next, on the first and seventh days, the stratum corneum was observed at the application site of the same human subjects. For observation of the stratum corneum, an adhesive tape for stratum corneum diagnosis (Keratin Checker AST-01, Nippon Ash Co., Ltd.) was pressed against the skin to sample the stratum corneum, which was then immersed in a staining solution (0.5 g of brilliant green and 1 g of gentian violet dissolved in 25 mL of ethanol, mixed with 75 mL of water) for 20 minutes, after which the staining solution was washed off with water and the sample was immersed in water for a further 20 minutes, sealed in glycerin, and observed under a microscope.

The results are shown in Figure 6. The large blue lumps are dried, peeling skin desquamation. By the seventh day in Preparation Example 1, almost no desquamation was visible. On the other hand, by the seventh day in Comparative Example 1, scattered desquamation was visible.

In the observation of the stratum corneum, a difference was observed between Comparative Example 1 and Preparation Example 1. This shows that even if the moisture content of the stratum corneum is approximately the same, there is a difference in the repair state of the stratum corneum.

According to the present invention, it has been found that by incorporating a heparinoid and ceramide, more specifically a heparinoid and N-stearoyldihydrosphingosine, into a water-in-oil emulsion composition and applying the composition to the skin, a high moisturizing effect continues to be exerted for a long period of time, and the water-in-oil emulsion composition can be provided. Furthermore, it has been found that by applying the water-in-oil emulsion composition to dry skin, a healing effect is exerted in a short period of time, and further, by blending a combination of (1) octyldodecanol or (2) triglyceride and N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide to dissolve N-stearoyldihydrosphingosine, syneresis can be prevented and a stable water-in-oil emulsion composition can be obtained.

Claims (19)

A water-in-oil emulsion composition containing a heparinoid and ceramide. The water-in-oil emulsion composition according to claim 1, wherein the ceramide is N-stearoyldihydrosphingosine. The water-in-oil emulsion composition according to claim 1 or 2, wherein the heparinoid content is 0.1-0.5% by mass, and the N-stearoyldihydrosphingosine content is 0.1-1% by mass. Plus any of the following ingredients:
(1) Octyldodecanol,
(2) triglyceride and N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide,
3. The water-in-oil emulsion composition according to claim 1 or 2, comprising: (1) The water-in-oil emulsion composition according to claim 4, containing 3.0% by mass or less of octyldodecanol. The water-in-oil emulsion composition according to claim 4, wherein the triglyceride in (2) is selected from the group consisting of glyceryl tri-2-ethylhexanoate, glyceryl tri(capryl-capric acid), and medium-chain fatty acid triglycerides. The water-in-oil emulsion composition according to claim 4, wherein (2) contains N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide in an amount 1.3 times or more by mass relative to the amount of ceramide. Any of the following ingredients:
(1) Octyldodecanol,
(2) triglyceride and N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide,
A stabilizer for a water-in-oil emulsion composition containing a heparinoid and a ceramide, comprising: The stabilizer for a water-in-oil emulsion composition according to claim 8, wherein the ceramide is N-stearoyldihydrosphingosine. The stabilizer for a water-in-oil emulsion composition according to claim 8 or 9, wherein the heparinoid content is 0.1 to 0.5% by mass, and the N-stearoyldihydrosphingosine content is 0.1 to 1% by mass. (1) A stabilizer for a water-in-oil emulsion composition according to claim 8 or 9, containing 3.0% by mass or less of octyldodecanol. The stabilizer for a water-in-oil emulsion composition according to claim 8 or 9, wherein the triglyceride in (2) is selected from the group consisting of glyceryl tri-2-ethylhexanoate, glyceryl tri(caprylate/caprate), and medium-chain triglyceride. The stabilizer for a water-in-oil emulsion composition according to claim 12, wherein (2) contains N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide in an amount 1.3 times or more by mass relative to the amount of ceramide. A water-in-oil emulsion composition containing a heparinoid and a ceramide, comprising any one of the following components:
(1) Octyldodecanol,
(2) triglyceride and N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide,
A method for stabilizing a water-in-oil emulsion composition containing a heparinoid and a ceramide by including therein. The method according to claim 14, wherein the ceramide is N-stearoyldihydrosphingosine. The method according to claim 14 or 15, 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. (1) The method according to claim 14 or 15, wherein the content of octyldodecanol is 3.0% by mass or less. The method according to claim 14 or 15, wherein the triglyceride in (2) is selected from the group consisting of triglyceride 2-ethylhexanoate, tri(caprylic/capric acid)glyceride, and medium-chain fatty acid triglyceride. The method according to claim 18, wherein in (2), N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide is contained in an amount 1.3 times or more by mass relative to the ceramide.