JPH08208423A - Dermal preparation for external use - Google Patents

Abstract

PURPOSE: To obtain a dermal preparation for external use, capable of reproducing the water holding functions possessed by the skin horny layer on the skin, effectively supplementing water to the skin or preventing water from evaporating from the skin and effective in improving skin symptoms, treating dermatopathy and prevention thereof. CONSTITUTION: This skin preparation for external use is obtained by preparing a lipid bimolecular membrane using a glycerophospholipid, a sphingophospholipid, a glyceroglycolipid, a sphingoglycolipid, etc., adding and compounding one or more selected from proline, leucine and isoleucine and one or more water-soluble polymers therewith, forming the resultant compounded lipid bimolecular membrane into a multilamellar layer (lamellar) structure such as a liposome, adding and dispersing the prepared lamellar structure in a base used in a preparation for external use. When the preparation is applied to the skin, the compounded lipid bimolecular membrane forms a lamellar layer on the skin, and suppressing effects on an increase in amount of combined water and evaporation of water are recognized in the lipid bimolecular membrane. As a result, xerotic symptoms of the skin can effectively be improved.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention protects skin from dryness and reduces skin moisture by hydrating the skin with good water retention or controlling transpiration of water from the skin. The present invention relates to an external preparation for skin that can prevent or improve the deterioration of skin symptoms or diseases caused by.

[0002]

2. Description of the Related Art In order to prevent the skin from drying and prevent or ameliorate the deterioration of the skin condition and the skin diseases caused by the decrease in the amount of water in the skin, moisturizers such as amino acids and polyhydric alcohols have been conventionally compounded. Provides a skin external preparation with improved water retention on the skin and an emollient such as ester oil and higher alcohol to form an oil film on the skin to prevent water evaporation from the skin. It has been.

In addition, as the structure and moisturizing function of the stratum corneum present in the outermost layer of the skin have become clear in recent years, substances such as sphingolipids and ceramides that are present in the stratum corneum and protect against water evaporation from the skin may be added. Has been considered.

Further, it has been proposed to incorporate these substances in liposomes in order to enhance the percutaneous absorption of the moisturizing agent and to permeate into the skin substances that enhance the water retention function of the skin.

However, the commonly used moisturizers are hygroscopic substances, and their water retention capacity is not so high.
On the contrary, it has a drawback that it absorbs moisture from the skin under low humidity, which has the opposite effect, and absorbs moisture in the outside air under high humidity to give a sticky and unpleasant feeling. On the other hand, when an emollient is used, a sticky feeling becomes remarkable when the coating amount is increased to obtain sufficient occlusive property,
However, if the amount used is reduced, there is a problem that sufficient occlusion cannot be obtained.

[0006] Although intercellular lipids such as sphingolipids have an excellent occluding effect, there is a problem that it is difficult to obtain a stable preparation because of poor compatibility with other oily bases. Furthermore, when it is applied on the skin, it can be expected to have a blocking effect on water evaporation from the skin, but it cannot be expected to have a water-retaining function in the state existing between corneocytes. Regarding the technology of encapsulating moisturizers and active ingredients in liposomes, it is difficult to keep the liposomes in a stable state in the formulation, and even if the liposomes are applied on the skin, the water-retaining function and water-transpiration prevention function of the stratum corneum Was difficult to reproduce.

[0007]

DISCLOSURE OF THE INVENTION The present invention solves the above-mentioned problems of the conventional external preparation for skin for the purpose of moisturizing, and provides the water retention function or the water evaporation protection function of the stratum corneum on the skin. The purpose of the present invention is to provide an external preparation for skin that can be almost completely reproduced, to improve and even prevent deterioration of skin diseases and skin conditions caused by dry skin.

[0008]

For the purpose of solving the above-mentioned problems, the present inventors have prepared a lipid bilayer by incorporating at least one selected from amino acids, higher fatty acids and higher alcohols into a complex. It was found that when a lamellar structure composed of a lipid bilayer is formed on the skin, water evaporation from the skin can be suppressed and the amount of bound water increases, which has already been disclosed (Patent application No. 6-1023
31). This time, by combining one or more kinds selected from proline, leucine, and isoleucine among amino acids with one or more kinds of water-soluble polymers to form a complex with a lipid bilayer membrane, It was found that the holding function was significantly improved, and the present invention was completed.

The lipid bilayer is composed of phosphatidylcholine,
Glycerophospholipids such as phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol, sphingolipids such as sphingomyelin, glyceroglycolipids such as glucosylacylglycerol, phosphoglyceroglycolipids such as phosphatidylglucosylacylglycerol, sphingosugars such as glucocerebrosides, and galactocerebrosides. It can be prepared using lipids. The lipid is dissolved by heating at 80 to 90 ° C. with stirring, and a solution of proline, leucine or isoleucine and a water-soluble polymer is added and contained. The added amount is proline,
For leucine and isoleucine, one or two or more of them are contained in a total amount of 1 to 20% by weight of the lipid bilayer membrane complex, and for water-soluble polymers, the total amount is 0.05 to 0.05 of the lipid bilayer membrane complex.
About 1.0% by weight is suitable. If the amount is less than the above amount, a sufficient water retention function or water evaporation prevention function cannot be exhibited, and conversely, if the amount exceeds the above amount, the stability of the preparation and the feeling of use of the external preparation for skin are affected.

As the proline, leucine or isoleucine, the naturally occurring L-form, D-form or DL-racemic form can be used. As water-soluble polymer,
Those having an anionic functional group such as a hydroxyl group or a carboxyl group are suitable for the purpose of the present invention, and particularly polyacrylic acid and its salts, carboxyvinyl polymer and its salts, hydroxyethyl cellulose, carboxymethyl cellulose and its salts, hyalurone. Acids and salts thereof are preferable, and one kind or a combination of two or more kinds is mixed from these.

Therefore, in the present invention, the lipid bilayer is combined with one or more kinds of proline, leucine and isoleucine and one or more kinds of water-soluble polymer to form a complex. The product is incorporated into a skin external preparation base. Such a complex lipid bilayer membrane can stably exist by taking a layered (lamellar) structure of a multi-layer membrane when blended in a base for external preparation. The complex lipid bilayer membrane can also be blended as spherical liposomes.

[0012]

[Function] The water-retaining function of the complex lipid bilayer membrane compounded in the external preparation for skin according to the present invention is shown below. That is,
To hydrogenated soybean phospholipid containing 30% by weight of hydrogenated soybean phospholipid containing 15% by weight of L-proline and 10% by weight of L-isoleucine, 25% by weight of 1% by weight aqueous solution of the water-soluble polymer shown in Table 1 was added. Was made into a composite, and this was made 100% by weight with purified water to obtain a sample. However, with respect to sodium polyacrylate, 25% by weight of a 0.25% by weight aqueous solution was added. 50 mg of these samples were applied to a membrane filter and placed on a vial containing water, and the amount of water contained in the membrane filter was measured with a near infrared moisture meter over time. At that time, as a control, an L-proline, L-isoleucine complexed lipid bilayer membrane to which a water-soluble polymer was not added was used. The measurement was performed 5 times, and the average value for each sample and control is shown in FIG.

[Table 1]

From FIG. 1, it can be seen that L-proline and
By adding a water-soluble polymer in addition to L-isoleucine to form a complex, the decrease in water content over time is less than that of a control in which L-proline and L-isoleucine are simply combined. It is recognized that the retention function is increased.

Subsequently, in the complex lipid bilayer membranes of the above-mentioned sample and control, the amount of bound water contained in a state not diluted with purified water was measured by measuring the enthalpy of fusion of free water using a differential scanning calorimeter. I asked. The results are shown in Figure 2.

In FIG. 2, in the complex lipid bilayer membrane (1 and 2) using sodium polyacrylate and carboxyvinyl polymer as the water-soluble polymer, the control (6)
The amount of bound water was significantly higher than that of. Also in the lipid bilayer membranes (3, 4 and 5) in which hydroxyethyl cellulose, carboxymethyl cellulose and hyaluronic acid are complexed, a slight increase in the amount of bound water was observed. Therefore, it is suggested that the increase in the water retention function of the complex lipid bilayer membrane shown in FIG. 1 is also due to the increase in the amount of bound water.

When the external preparation for skin according to the present invention is thinly applied to a skin piece and observed with a polarizing microscope, the formation of a lamella layer composed of a lipid bilayer membrane is recognized. Therefore, when the external preparation for skin according to the present invention is applied on the skin, a lamella layer of the complex lipid bilayer is formed on the skin, which covers the skin and suppresses the evaporation of water, and has a good water retention function. It is considered that it exerts the action of supplying the necessary moisture to the skin to prevent it from drying out.

[0017]

EXAMPLES The present invention will be described in more detail with reference to Examples. Examples 1 to 3 are skin creams according to the present invention. These formulations are shown below. As the complex lipid bilayer membrane in each example, those having the compositions of Preparation Example 1, Preparation Example 2 and Preparation Example 3 in Table 2 were used. These lipid bilayers were dispersed in the cream base in a layered lamella structure.

Skin cream (1) Stearic acid 1.00 (% by weight) (2) Stearyl alcohol 4.00 (3) Glycerin monostearate 3.00 (4) Hydrogenated castor oil 7.00 (5) Squalane 10 0.000 (6) Safflower oil 2.00 (7) Sorbitan sesquioleate 1.00 (8) Sodium hydroxide 0.05 (9) Pullulan 0.10 (10) Methyl paraoxybenzoate 0.10 (11) Purified water 66.25 (12) Complex lipid bilayer 5.00 (13) Perfume 0.50 (1) to (7) were heated and dissolved at 75 ° C., and then dissolved at 75 ° C. (8) ~ (11) is added to emulsify, cool and at 40 ℃
(12) and (13) are added, and further cooled to room temperature to prepare. Here, in place of the complex lipid bilayer membrane of (12), a liposome prepared by only hydrogenated soybean lecithin was compounded with Comparative Example 1, L-proline 15% by weight and L-isoleucine 10% by weight. What used the said lipid bilayer membrane was made into the comparative example 2.

Examples 4 to 7 are skin emulsions according to the present invention. These formulations are shown below. In each Example, the compositions of Preparation Example 4, Preparation Example 5, Preparation Example 6 and Preparation Example 7 in Table 2 were used as liposomes.

Emulsion for skin (1) Stearic acid 0.50 (% by weight) (2) Cetanol 1.50 (3) Glycerin monostearate 2.00 (4) Squalane 5.00 (5) Jojoba oil 1.00 (6) Sorbitan sesquioleate 0.50 (7) 1,3-butylene glycol 5.00 (8) Sodium hydroxide 0.02 (9) Methyl paraoxybenzoate 0.10 (10) Purified water 81.28 ( 11) Complex lipid bilayer 3.00 (12) Perfume 0.10 (1) to (6) were heated and dissolved at 75 ° C, and (7) to (10) which was heated and dissolved at 75 ° C were added thereto. Emulsify and cool at 40 ° C
(11) and (12) are added, and further cooled to room temperature to prepare. Here, in place of the complex lipid bilayer membrane of (11), a liposome prepared only with hydrogenated soybean lecithin was compounded with Comparative Example 3, 15% by weight of L-proline and 10% by weight of L-isoleucine. What used the said lipid bilayer membrane was made into the comparative example 4.

Examples 8 to 10 are skin lotions according to the present invention. These formulations are shown below. In each example, the compositions of Preparation Example 8, Preparation Example 9 and Preparation Example 10 in Table 2 were used in the form of liposomes.

Skin lotion (1) Polyoxyethylene (20) sorbitan 1.0 (wt%) monolaurate (2) 1,3-butylene glycol 3.0 (3) sorbitol 2.0 (4) ethanol 5.0 (5) Complex lipid bilayer 2.0 (6) Methyl paraoxybenzoate 0.1 (7) Xanthan gum 1.0 wt% aqueous solution 10.0 (8) Perfume 0.2 (9) Purified water 76.7 Mix all components except (5), dissolve to homogeneity, then (5)
Are prepared by dispersing. Here, in place of the complex lipid bilayer membrane of (5), a liposome prepared only with hydrogenated soybean lecithin was compounded with Comparative Example 5, L-proline 15% by weight and L-isoleucine 10% by weight. What used the said lipid bilayer membrane was made into the comparative example 6.

[Table 2]

Human use tests were conducted on the above-mentioned Examples and Comparative Examples. 20 patients with serious skin symptoms caused by dry skin were set as one group, and each sample of Example and Comparative Example was continuously used in blind for 4 weeks, and the improvement status of skin symptoms was observed. . For skin symptoms, the appearance of dryness, cracks, desquamation, and wrinkles of the skin is visually judged, and 4 points in the case of severity and 3 points in the case of moderate degree.
An average value of 20 subjects was calculated by scoring points, 2 points for mildness, 1 point for slightly observed symptoms, and 0 point for no symptoms. The results are shown in Tables 3 to 5 together with the evaluation of the skin condition before use. The occurrence of erythema and swelling in each group was also observed at the same time.

In Table 3, even in the group using the cream of Comparative Example 1, dry skin symptoms were improved, but still mild to moderate symptoms were observed. Further improvement was observed in the group using the cream of Comparative Example 2, but the symptoms were still clearly observed, and in particular, regarding “wrinkles”, the degree was improved to almost mild degree. On the other hand, in the group used in the Examples, there were some panelists who recovered from all symptoms, and even if they did not recover, the symptoms were slightly observed.

[Table 3]

Also in Table 4, the effect of improving the dry symptom of the group used in the Examples is large, and most of the patients who have symptoms close to the severity of the overall findings have recovered to the level of complete or slight symptom. This was in contrast to the comparative example 3 in which the symptoms were alleviated to a moderate degree in the overall findings. In the group used in Comparative Example 4 as well, the dry symptom was improved to almost a mild degree, but it was not as high as that observed in the group used in Example.

[Table 4]

In Table 5, since the sample is in the form of a lotion, the effect of blocking the skin is small, and in the group of Comparative Example 5 used, the symptom is only reduced to a moderate degree. In the group used in Comparative Example 6 as well, an improvement was seen to a degree of mildness, but in the group used in Example, it was reduced and improved to such an extent that a dry symptom was slightly observed. It has been shown that a sufficient improvement effect can be obtained.

[Table 5]

In addition, no erythema or swelling was observed in any of the groups used in the above Examples and Comparative Examples.

In each of the examples, the lamellar lamellar structure composed of the complex lipid bilayer and the liposome were stably retained for 3 months or longer in the skin external preparation base. It was confirmed that when applied on a piece of skin, a relatively stable lamellar lipid bilayer membrane was formed.

[0029]

As described above in detail, by using the external preparation for skin according to the present invention, it is possible to form a lamellar layer of a lipid bilayer having a water retaining function and an occluding function on the skin. The layer exerted the same physiological action as the intercellular lipids present in the stratum corneum, and it became possible to effectively protect the skin from dryness. As a result, it improves various skin symptoms caused by dryness such as cracks, desquamation, and wrinkles, effectively treats skin diseases caused by dryness such as senile xerosis, and effectively prevents such symptoms and diseases. I was able to. Further, the external preparation for skin according to the present invention had good formulation stability, no skin irritation or sensitization such as erythema or swelling was observed, and there was no problem in safety.

[Brief description of drawings]

FIG. 1 is a lipid complexing L-proline and L-isoleucine, which does not complex a water-soluble polymer, with the water-retaining function of the complex lipid bilayer membrane (Sample 1 to Sample 5 in Table 1) used in the present invention. It is a figure which contrasts and shows a bilayer membrane.

FIG. 2 shows the amount of bound water of a complex lipid bilayer membrane (Sample 1 to Sample 5 in Table 1) used in the present invention, which is obtained by complexing L-proline and L-isoleucine and not complexing a water-soluble polymer. It is a figure which contrasts and shows a molecular film.

[Explanation of symbols]

 1 Complexed Lipid Bilayer of Sample 1 2 Complexed Lipid Bilayer of Sample 2 3 Complexed Lipid Bilayer of Sample 3 4 Complexed Lipid Bilayer of Sample 4 5 Complexed Lipid Bilayer of Sample 5 6 Controlled complex lipid bilayer

Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display area A61K 9/127 D

Claims (4)

[Claims] 1. A skin comprising a lipid bilayer membrane containing one or more selected from proline, leucine and isoleucine and one or more kinds of water-soluble polymers. Topical agent. 2. The water-soluble polymer is selected from the group consisting of polyacrylic acid and salts thereof, carboxyvinyl polymer and salts thereof, hydroxyethyl cellulose, carboxymethyl cellulose and salts thereof, hyaluronic acid and salts thereof. The external preparation for skin according to claim 1. 3. The external preparation for skin according to claim 1, wherein the lipid bilayer has a multilamellar structure (lamella). 4. The external preparation for skin according to any one of claims 1 to 3, wherein the external preparation for skin is a cosmetic.