KR19990078610A - Skin Care Composition For Improvement Of The Water-retaing Capacity Of The Skin And Restoration Of a Damaged Skin - Google Patents

Abstract

An object of the present invention is to provide a composition for skin care having the same composition and structural properties as the skin cell membrane and a method for producing the same in order to fully exhibit the efficacy of ceramide and spinolipid. .

The composition of the present invention is composed of the main components of the stratum corneum cells, ceramides, cholesterol, fatty acids, lecithin, triglycerides, and phytospinosine or its derivatives, which are the main components of the skin endothelial cell membrane.

The skin protection composition prepared by the present invention has no side effects and excellent skin permeability and moisturizing ability compared to the product of ceramide mixed with the skin cell membrane and other compositions. This can be said that the composition of the present invention greatly reduces the water loss of the stratum corneum layer to improve the skin barrier function, excellent moisturizing effect. In addition, its compatibility with other hydrophobic or water-soluble therapeutic active ingredients (Therapeutic Active Ingrediens), as well as excellent drug delivery, has been proven to be effective in healing acne and skin wounds.

Description

Skin Care Composition For Improvement Of The Water-retaing Capacity Of The Skin And Restoration Of a Damaged Skin}

The present invention relates to a composition for protecting skin having the same lipid composition and structural properties as a biological membrane present in human intercellular skin (Intercellular).

In order to develop the most desirable skin application products for maintaining a healthy skin condition, it is desirable to fully understand the structure of the skin and the biofilm composition and physical properties of skin cells.

The structure of the skin is divided into dermis, epidermis and stratum corneum according to differentiation of keratinocyte cells from the basal layer.

The intercellular skin composition has a lipid lamellar bilayer structure and the lipid composition is changing according to the skin layer.

In particular, the stratum corneum, which is the outermost layer of skin, not only protects the skin primarily from the external physicochemical environment but also plays an important skin barrier function to prevent internal moisture loss. Dry skin can cause a variety of skin diseases, so keeping the skin moisturizing is the basis of skin protection.

It is also known that the skin is exposed to numerous external microorganisms and there is a skin composition in the stratum corneum to keep the skin in a normal state (Normal Bacterial Flora). Tannock, G.W., in "Normal Microflora" (Eds. Chapman & Hall), pp 3-8, 1995.

Therefore, studies have been undertaken over the past decade to identify lipid compositions present between stratum corneum cells and their physicochemical properties and biological functions.

In general, phospholipids (Phospholipids) is an important component that forms a lipid bilayer in the intercellular composition, but the composition of the cell membrane decreases the phospholipid content and increases the content of ceramide in the stratum corneum. The intercellular lipid composition is composed of 40% ceramide, 25% cholesterol, 25% fatty acid, and 10% cholesterol.

Ceramide is known as an important ingredient that prevents the loss of moisture in the stratum corneum and restores damaged skin protection layers.

Phytosphingosine, one of the precursors of ceramide, has recently been known to act as an antibiotic that keeps the skin in a normal state from microorganisms even though it is present in the stratum corneum (Bibel, DJ et al .: " Topical sphingolipids in antisepsis and antifungal threapy: Clinical and Experimental Dermatology "1995; 20, pp 395-400. -Bibel, DJ et al.:"Antimicrobial Activity of Stratum Corneum Lipids from Normal and Essential fatty Acid-Deficient Mice": J Invest Dermatol 92: 632-638,1989.- Bibel, DJ et al .: "Antimicrobial Activity of Sphingosines: J Invest Dermatol 98: 269-273, 1992)

In addition, various skin diseases such as atopic dermatitis are known to be caused by abnormal changes in lipid composition constituting the lipid protective film of the stratum corneum, and development of products combining ceramides, cholesterol, and fatty acids, which are important components of cell membranes, has been developed in Dermatology field. (Mao-Qiang M.Feingold KR.Thornfeldt CR, Elias PM: "Optimization of physilogical lipid mixtures for barrier repair. J Invest Dermatol 106: 1096-1101, 1996).

Due to these reasons, much research is being conducted on the development of skin protection products using lipids and phytospinosine in the stratum corneum. In order for these substances to exhibit sufficient physiological activity, they must pass through the stratum corneum and through the skin endothelial cell membrane consisting of phospholipids. To this end, it is necessary to develop a lipid layer (Lipid Lamellar) product having a structure similar to the skin cell membrane.

However, due to the hydrophobicity of ceramide and phytospingosin, the solubility is low and it is easy to crystallize, so the amount of usage is limited, and due to the use of solvents and various additives that are not suitable for skin such as propylene glycol / ethanol Side effects and problems with skin permeability have resulted (-De Paepe K, Vandamme P, Roseeuw D, Rogiers V: Ceramides / Cholesterol / free fatty acids containing cosmetics: The effect on the barrier function.S? W-Journal 122: 199 -204, 1996.- de Groot AC, Weyland JW, Nater JP: Unwanted effects of cosmetics and drugs used in dermatology.In: de Groot AC, Weyland JW, Nater JP (eds.). Elsevier, Amsterdam, 1994, 3rd. ed, pp 770).

In order to solve this problem, products having synthesized pseudo ceramide (Pseudo Ceramide) similar to solubility and ease of use of ceramides have been produced, but these products have a disadvantage in that they are easily accumulated in the skin and are not biodegradable.

Therefore, in order to fully demonstrate the effects of ceramide and phytospinosine on the skin, a special formulation is required. As a solution to these problems, the present inventors have excellent skin affinity, that is, the same composition as that of the skin cell membrane. To develop a composition for protecting the skin having structural properties.

An object of the present invention is to provide a composition for skin care having the same composition and structural properties as the skin cell membrane and a method for producing the same in order to fully exhibit the efficacy of ceramide and spinolipid. .

The composition of the present invention is composed of the main components of the stratum corneum cells, ceramides, cholesterol, fatty acids, lecithin, triglycerides, and phytospinosine or its derivatives, which are the main components of the skin endothelial cell membrane.

As such, in the present invention, by using only natural substances present in the skin cell membrane and not using a solvent such as propylene glycol / ethanol or a synthetic surfactant, it is possible to develop a composition having high skin affinity and no side effects. It became.

Ceramide used in the present invention was used as a derivative of Spingosine (Sphingosine), Spinganine (Sphinganine), Phytosphingosine in pure form and a mixture of two or more. Groups of ceramides 1, 2, 3, 4, 5, 6I, 6II are also included.

(Ceramide derivative used in the present invention)

1.Spin high reductant

2. Spinganine Derivatives

3. Phytospinosine derivatives

R is a saturated and unsaturated fatty acid having 6 to 25 carbon atoms. In the case of unsaturated fatty acids, R has 1 to 2 double bonds, and in the case of saturated fatty acids, R has a hydroxyl group at the α or β position.

Although phytospinosine used in the present invention is used as such, it can be used by modifying the derivative having the following polarity to increase the emulsification power and water solubility of phytospinosine.

Organic salt

Organic salts were used to make organic salts with neutral pH. The organic acids used were hydrogen chloride, lactic acid and other α- or β-hydroxy acid and salicylic acid.

2. cation

N, N, N-trimethyl phytosphingosine was synthesized by introducing a methyl group to the amine group of phytospingosin.

Tetraacetylphytosphingosine (TAPS)

It was synthesized from phytospinosine and used.

Cholesterol and its derivatives used in the present invention assist in the formation of liquid crystals (Liquid Lamellar Crystallization) of ceramides having the same structure as the skin cell membranes and stabilize the liquid crystals. Cholesterol, cholesterol, cholesterol hemisuccinate (Cholesterol hemisuccinate) Was used.

As the fatty acid used in the present invention, a saturated or unsaturated fatty acid having 6 to 25 carbon atoms was used alone or as a mixture of two or more thereof.

Phospholipids used in the present invention were hydrogenated and hydroxide phospholipids in consideration of product stability as a penetration enhancer and an emulsifier.

The mixture thus prepared had no side effects and had excellent skin permeability and moisturizing properties compared to the product of ceramide mixed with the skin cell membrane and other compositions. In addition, it is compatible with other hydrophobic or water-soluble therapeutic active ingredients (Therapeutic Active Ingrediens) as well as excellent drug delivery, it can be used as a pre-formulation of the product for the treatment of skin wounds.

The present invention relates to a composition for protecting the skin having the same composition and structural properties as the skin cell membrane and a method for producing the same in order to sufficiently exhibit the efficacy of ceramide, phytospinosine and derivatives thereof.

The composition of the present invention is composed of the main components of the stratum corneum cells, ceramides, cholesterol, fatty acids, lecithin, triglycerides, and phytospinosine or its derivatives, which are the main components of the skin endothelial cell membrane.

The lipid composition of the stratum corneum is known to be associated with various skin diseases, and research has been focused on restoring the cell membrane by supplying ceramides, cholesterol, and fatty acids, which are the main components of the cell membrane, to damaged skin. Ceramide, cholesterol, and fatty acids, which are stratum corneum lipids, are mixed in an appropriate ratio to form liposomes, which are a type of liquid crystal, and are used in research on drug delivery systems related to skin.

However, the hydrophobic (Hydrophobic) of the ceramide, which is known as the most important component, and the crystallization in the mixture have been well formed, so there were many difficulties in developing a product having excellent stability, usability and permeability. In order to solve this problem, the present invention uses only natural materials present in the skin cell membrane and does not use synthetic surfactants and solvents to protect the skin with oil-in-water (O / W) type liquid crystals having excellent skin affinity and no side effects. The composition was developed.

Ceramides used in the present invention are amide derivatives in which fatty acids are introduced into amine groups of spinosine, phytospinosine and spinganine.

(Ceramide derivative used in the present invention)

1.Spin high reductant

2. Spinganine Derivatives

3. Phytospinosine derivatives

R is a saturated and unsaturated fatty acid having 6 to 25 carbon atoms, and in the case of unsaturated fatty acid, R has 1 to 2 double bonds, and in the case of saturated fatty acids, R has a hydroxyl group at the α or β position.

The ceramide derivative is preferably used in the range of 1 to 10% by weight of the composition of the present invention so as to form a stable emulsion.

Triglyceride and lecithin used in the present invention are used in 1 to 10% by weight of the composition of the present invention.

Cholesterol used in the present invention is selected from the group consisting of cholesterol, cholesterol sulfate and cholesterol hemisuccinate. The addition of cholesterol helps the formation of liquid crystals and increases the stability of the liquid crystals formed. The amount of cholesterol is preferably used up to 1 to 10% by weight of the composition, most preferably when used in the range of 40 to 50% by weight relative to the ceramide weight ratio.

The fatty acids used in the present invention were used alone or in combination of two or more unsaturated fatty acids having 1 to 2 carbon atoms in saturated or double bonds having 6 to 25 carbon atoms. The fatty acid may be used in an amount of 1 to 10% by weight of the composition, but the most effective amount is when used in the range of 40 to 50% by weight based on the weight of ceramide.

In the preparation of the composition of the present invention, the most effective ratio of forming liquid crystals with stratum corneum lipids is when using ceramide: cholesterol: fatty acid in a 2: 1: 1 weight ratio. That is, when applying the cosmetic composition formed in such a ratio to the skin, the restoration of the damaged skin protection film can be effectively promoted.

The phytospinosine used in the present invention is 1) used alone as phytospinosine or 2) as an organic salt form using an organic acid to increase solubility and emulsification power, or 3) introducing a methyl group to the amine group of phytospinosine N, It can be used in the form of N, N-trimethylphytospinosine or 4) Tetraacetylphytosphingosine (TAPS). It can be used within the range of 1 to 10% by weight of the composition.

1.organic salts

Organic acids were used to make organic salts with a neutral pH. The organic acids used were α- or β-hydroxy acids, such as hydrogen chloride and lactic acid, and salicylic acid. Although these acids are known to activate skin cells, they are difficult to use in skin care products because of their high acidity.

2.Cation

N, N, N-trimethylphytosphingosine was synthesized by introducing a methyl group to the amine group of phytospinosine.

3. Tetraacetylphytosphingosine (TAPS).

It was synthesized from phytospinosine and used.

Phytospinosine is present in a small amount of less than 1% by weight in the stratum corneum of the stratum corneum, but it has antimicrobial activity, which contributes to maintaining the normal healthy state of the skin from microorganisms, and is a bioactive substance that serves as a precursor of ceramide formation. Healing experiments through the subjects with acne for the composition prepared in the present invention was able to demonstrate a good effect.

Lecithin is an important component of biomembrane, which is the most used substance for drug delivery system research due to the formation of lipid bilayer and liposomes in water. In addition to these applications, it is also used as an emulsifier (Skinner) and Skin Penetration Enhencer to soften rough skin.

In the lecithin used in the present invention, phospholipids having about 20 iodine (Iodine Value) of hydrogenation or hydroxide (Hydroxylation) were used in consideration of oxidative stability.

The composition used in the present invention formed vehicles (Vehicles) that can capture the active material on the skin. This property can be used as a pre-formulator for skin protection products using therapeutic agents.

(Method for producing ceramide derivative)

1.Method of manufacturing organic salt of phytospingosin

Phytospingosin is dissolved in ethanol and an equivalent amount of organic acid is added. After stirring at room temperature for 30 minutes, the ethanol was removed under reduced pressure, and then the resultant precipitate was filtered and dried (yield: 98% by weight).

2. Preparation of N, N, N, -trimethylphytospinosine

Phytospingosin is dissolved in chloroform (Chloroform) solvent, and then 5 equivalents of sodium carbonate (Sodium Carbonate) and methyl iodide (Methyl Iodide) are added and refluxed for 7 hours. The precipitate was filtered off, the solvent was removed under reduced pressure, and acetone was added to the residue. The resulting precipitate was collected by filtration and dried to obtain the desired material. (Yield: 70% by weight)

3. TAPS

Phytospingosin is dissolved in anhydrous chloroform, and then 5 equivalents of triethylamine are added and cooled to room temperature.

5 equivalents of Acetylanhydride is added to the reaction vessel for 30 minutes, followed by stirring under reflux for 4 hours. After cooling to room temperature, the reaction solution and the same amount of water are added to separate the organic layer. After three repetitions, the organic solvent is blown off under reduced pressure, and hexane is added to the residue, followed by recrystallization. The precipitate was filtered off to yield the desired material after drying. (Yield: 95% by weight).

Example 1

The skin protection composition of the present invention is prepared by dividing the lipid phase and the aqueous phase and then slowly adding the aqueous phase to the lipid phase. First, 1.5 g of stearic acid is added to 5 g of triglycerides, and a lipid phase is heated up to 80 degreeC. When the mixture is completely dissolved, 3 g of cholesterol. Add 5 g of ceramide and stir until dissolved. After adding 2 g of lecithin to dissolve, 1.5 g of oleic acid is added. The aqueous phase raises 79.2 g of distilled water to 80 degreeC. Add 2 g of phytospingosin and 0.8 g of lactic acid and stir until complete dissolution. The dissolved aqueous phase was slowly added to the lipid phase, stirred at 80 ° C. for 30 minutes, and then cooled slowly at room temperature to obtain a creamy composition.

Example 2

In the same manner as in Example 1, 2 g of stearic acid is added to 5 g of triglyceride to raise the temperature to 80 ° C. When the mixture is completely dissolved, 3 g of cholesterol. Add 5 g of ceramide and stir until dissolved. The aqueous phase raises 82.3.g of distilled water to 80 degreeC. Add 2 g of phytospingosin and 0.7 g of lactic acid and stir until complete dissolution. The dissolved aqueous phase was slowly added to the lipid phase, stirred at 80 ° C. for 25 minutes, and then cooled slowly at room temperature to obtain a creamy composition.

Example 3

The lipid phase is heated to 80 ° C by adding 1 g of stearic acid to 3 g of triglycerides. When the mixture is completely dissolved, 3 g of cholesterol, 2 g of TAPS and 5 g of ceramide are added and stirred until dissolved. After adding 2 g of lecithin to dissolve, 1 g of oleic acid and 1 g of linoleic acid are added gradually under stirring. The water phase is heated to 80g of distilled water and then stirred until it is completely dissolved by adding 2g of Phytosphingosine ?? Hcl. The dissolved aqueous phase was slowly added to the lipid phase, stirred at 80 ° C. for 30 minutes, and then cooled slowly at room temperature to obtain a creamy composition.

The composition prepared according to the present invention can be applied to human skin, and especially when the skin is dry or damaged, it can be used as a material to reduce the escape of water from the skin and to restore the cell membrane of the damaged skin.

Test Example 1 Acne healing effect and skin moisturizing effect of the composition (Example 1) of the present invention

The skin was tested on 15 young men who had more than 10 comedones on one cheek. As a result of applying the skin composition of the present invention prepared in Example 1 to the face three times a day before breakfast, lunch, and soaking every day at an appropriate time every day, 6 to 12 weeks elapsed depending on the person, visually observing the acne area. I could do it.

After three weeks, the acne area subsided to some extent, and then the electrical conductivity was measured using a liquid hydrometer (Skin Surface Hydrometer. Skicon-200. Ibs Inc., Japan).

Table 1. Electrical conductivity measurement result

Electrical Conductivity (μΩ ¹ ) Before treatment After treatment 51.2 ± 6.6 200.5 ± 9.7`

In addition, after 3 weeks, water loss through the stratum corneum (TEWL, Trans-Epidermal Water Loss) was measured using an evaporation meter (Evaporimeter, Epi. Servo Med. Sweden).

Table 2. Moisture loss measurement result

Water loss (TEWL) Before treatment After treatment 50.5 ± 2.5 10.1 ± 3.2

As can be seen from the table, the skin cured with the composition of the present invention can be seen that the water loss is significantly improved compared to before treatment. This can be said that the composition of the present invention greatly reduces the water loss of the stratum corneum layer to improve the skin barrier function, excellent moisturizing effect.

Test Example 2 Wound Healing Effect of the Composition of the Present Invention

2-1 Efficacy test on stab of composition (Example 1)

By measuring the tension strength of the pierced wound (skin wound) by measuring the degree of injury of the wound to determine the efficacy of the wound treatment. This method was implemented with some modifications of Schulte and Domenjoz's method.

Sprague-Dawley male rats of constant weight are used, and the breeding environment is adapted for at least one week at a temperature of 22 ± 2 ℃ and a humidity of 50 ± 5%, and then selected and used as experimental animals without general signs of abnormality. It was. During the preliminary breeding and experiment period, water and feed were freely ingested. During the experimental period, all experimental animals were raised in individual cages. The experimental groups were divided into five groups for each group as shown in Table 1. Blank group was administered nothing, and the control group was administered to the base (Ointment base) used as the ointment base (Base) in pharmacies or hospitals.

The hair on the rat's back is clipped with a clipper, the skin is disinfected with 70% alcohol under ether anesthesia, and a surgical knife is placed on the back skin along the midline from 3 cm away from the neckline. 2cm incision was made and sutured at 0.5cm intervals. To prevent infection, antibiotics were injected once daily for 4 days (i.m. = Intra-Muscular Injection). The test substance was applied once a day from the day of surgery. Five days after the operation, the suture was removed, and the skin including the wound was removed on the seventh day of surgery, and the tension of the wound was measured by a tension meter (CKKim et al. J. Kor. Pharm. Sci., Vol. 27. No. 2.139-143,1997), (R. Schulte and R. Domenjoz. Med. Pharmacol.Exp. 16. 453-458,1967)

The measured results are shown in the table below.

From the results shown in the table, it was found that the wound healing effect of the composition of the present invention (Example 1) was overshadowed, and the wound healing effect of the control group was higher than that of the Blank group, which may be due to the basic moisturizing effect of the ointment.

Table 3. Tension Measurement Results

Test group tension (% by weight) Blank group 100 coarse cream group 125 invention (Example 1) 150

Test Example 3 Wound Healing Effect by Wound Area Measurement Method

The effect of wound healing is to be determined by measuring the restoration of the cut region of the skin in a 6mm diameter circle. This method was implemented by partially improving the method of Wakita et al.

Sprague-Dawley rats with a constant weight were used, and the breeding environment was adapted for at least one week at a temperature of 22 ± 2 ° C and a humidity of 50 ± 5%. During the preliminary breeding and experimental period, water and feed were freely ingested. During the experimental period, all experimental animals were raised in individual cages.

The hair on the back of the rat was clipped with a clipper, and the hair was exposed by shaving with a razor. After ether disinfection of skin with 70% alcohol, cut the midline into 3mm diameter circle with Biopsy Punch from 3cm away from the neckline to make trauma. To prevent infection, antibiotics were injected once daily for four days. The test substance was applied once a day from the day of surgery. The size of the wound was measured every 4 days, 7 days, and 10 days after the experiment, and the transparent film was closely adhered to the wound area, and the wound shape was accurately drawn to determine the area of the wound. The area measuring method used a method of measuring the weight of the pattern after copying a 400% enlarged copy using a copy machine on a constant copy paper. The treatment rate was calculated as follows.

* Treatment rate (%) = [1-(area weight of measurement date / 1st day area weight)] * 100

The experimental groups were divided into five groups for each group as shown in the table below. Blank group was administered nothing, and the control group was administered to the base (Ointment base) used as the ointment base (Base) in pharmacies or hospitals (H. Wakita. Et al. J. Invest. Dermatol. 110: 253-258, 1998)

The measured results are shown in the table below.

The results shown in the table showed that the wound healing effect of the composition (Example 1) of the present invention is superior.

Table 4. Wound Healing Effect by Wound Area Measurement

Test Group Treatment Rate (%) 4 days 7 days 10 days Blank group 15.2 43.4 80.2 Control cream group 16.6 52.7 92.5 Invention (Example 1) 22.5 61.0 96.2

As described above, the composition for protecting skin according to the present invention has no side effects and has excellent skin permeability and moisturizing power compared to a product in which ceramide is mixed with skin cell membrane and other compositions. This can be said that the composition of the present invention greatly reduces the water loss of the stratum corneum layer to improve the skin barrier function, excellent moisturizing effect. In addition, its compatibility with other hydrophobic or water-soluble therapeutic active ingredients (Therapeutic Active Ingrediens), as well as excellent drug delivery has been proven to be effective in healing acne and skin wounds.

Claims (10)

A skin protective composition comprising a skin lipid composition, wherein the composition is composed of ceramide, cholesterol, fatty acids, triglycerides, lecithin, phytospinosine or derivatives thereof. The composition of claim 1, wherein the ceramide, cholesterol, and fatty acid are used in the composition in a weight ratio of 2: 1: 1. According to claim 1, wherein the lecithin, phytospingosin and derivatives thereof is a skin protection composition, characterized in that used in 1 to 5% by weight of the composition. The composition of claim 1, wherein the ceramide is an amide derivative in which a fatty acid is introduced into an amine group of spingosin, spinganine, and phytospingosin, and is used in an amount of 1 to 10% by weight of the composition. The composition for protecting skin according to claim 4, wherein the fatty acid is a saturated and unsaturated fatty acid having 6 to 25 carbon atoms. The composition of claim 1, wherein the cholesterol is selected from the group consisting of cholesterol and sulfestol and cholesterol. The method of claim 1, wherein the cholesterol restoring composition for skin protection, characterized in that used in 1 to 10% by weight of the composition. According to claim 1, The phytospinosine derivative is used alone or in the form of an organic salt using an organic acid to enhance solubility and emulsification, or by introducing a methyl group to the amine group of phytospinosine N, N, N-tree Skin protection composition, characterized in that used in the form of methyl phytospingosin, or used in the form of Tetraacetylphytosphingosine (TAPS). The composition of claim 1, wherein the composition is used to heal skin damaged by burns or wounds. The composition of claim 1, wherein the composition is used for acne healing.