JP3262780B2 - Phytosphingosine aqueous solution, its production and use - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a clear aqueous solution by dissolving phytosphingosine with water at least 5% and at most 10% without using any solvent such as alcohol. Things. More specifically, 5% to 10% by weight of phytosphingosine is used.
After adding to distilled water at about the same concentration and stirring while heating the temperature to about 80 ° C, phytosphingosine is dissolved while neutralizing the pH with various acids such as lactic acid (Lactic Acid), After completely dissolving sphingosine, salicin (Salicin), salicylic acid (Salicylic Aci
The present invention relates to a method for producing a clear solution-like aqueous solution of phytosphingosine by adding 0.1 to 1% by weight of a willow bark extract containing 10% by weight or more of a salicylic acid-like substance such as d).

[0002]

[Prior Art] Phytosphingosi
ne) is a kind of sphingolipid, one of the major cell membrane components of living organisms, a signal transmitter of the signal transfer system along with its structural function, and a biologically active substance with various biological functions. (Okazaki et al., 1989; Ki
m et al., 1991). All sphingolipids in the body are sphingosine, phytosphingosine and sphinganine, sphingolipid bases (Sphingoid Long Chain B).
ase) as a basic skeleton, and a basic structure of ceramide in which a fatty acid is linked to an amino group of a sphingolipid base.

[0003] Sphingolipids regulate cell growth, proliferation, differentiation and apoptosis (apoptosis) by a newly revealed signal transduction process called the “sphingomyelin cycle”.
optosis) and have been shown to play a central role in life phenomena (Hannun, 1994, 199).
6; Hannun and Obeid, 1995), TNF-α, IL-
1, γ-IFN and FAS ligands were found to be involved. Sphingolipids make up the majority of skin lipids and function to moisturize the skin and regenerate the skin protective membrane, as well as function as the primary protective membrane of the skin against attack from microorganisms. In addition, sphingolipids inhibit and activate protein kinase C,
It is known to be involved in the regulation of receptor (Receptor) activity, induction of intracellular Ca ⁺⁺ ion mobilization, and regulation of Rb and NF-κB gene expression. I have. Recently, it has been found that most skin diseases including atopic dermatitis, in which 3 to 4% of the world's population are patients, are caused by reduced contents of various sphingolipids in skin lipids. Sphingolipids are a major raw material for the treatment of dermatosis, and are expected to be very likely to be used as next-generation pharmaceutical raw materials that can replace steroid hormones, which are antibiotics and anti-inflammatory agents.

Phytosphingosine-based ceramides III and IV have, over the last few years, begun to be used extensively as a major functional ingredient (Cosmeceutical) in the cosmetics industry. For example, ceramide (N-acylated sphingosine (N-acylated sphingosine) occupying 40% by weight or more of skin lipids) is used.
phingosine), N-acylated phytosphingosine (N-
Since acylated phytosphingosine has excellent skin moisturizing function and regenerating effect of damaged skin protective film, it is used worldwide for skin care cosmetics, and its use has been expanded to hair products. I have. Phytosphingosine has begun to be used together with ceramide as a functional ingredient such as a moisturizer and an anti-aging agent in the cosmetics industry, and has a rapid increase in its use because it has better skin regeneration, antibacterial and anti-inflammatory effects than ceramide. Also,
In the pharmaceutical industry, phytosphingosine has been considered as a therapeutic agent for atopic dermatitis, acne, and wounds. Regeneration products, atopic dermatitis treatment, acne treatment,
Its use is expected to be expanded to therapeutic agents for psoriasis and pruritus, wound healing agents and the like.

[0005] However, sphingolipids extracted and used from animals are difficult to use anymore due to mad cow disease and the like, and the method of producing using a pure synthetic method is too expensive, so that it is economical. Difficult to use. In addition, there are many cases where the stereochemical structure is different from that of sphingolipids present in the human body, and it has been difficult to obtain sphingolipids having a constant stereochemical structure. Phytosphingosine has recently been developed by a method of obtaining by yeast fermentation,
Phytosphingosine, obtained by yeast fermentation, was found to have a stereochemically identical structure to that present in the human body, and began to be used in many industries. Are also increasing rapidly. However, phytosphingosine obtained in large amounts by yeast fermentation has also had a limit in its use in cosmetic and pharmaceutical applications due to solubility problems. Furthermore, phytosphingosine is not soluble at all in water and only about 1% by weight in solvents such as isocetyl alcohol, which can be used as a raw material for cosmetics, so that it is effective when used as a raw material for functional cosmetics. There is a great difficulty in using a sufficient amount to obtain, and it has not been used at all in transparent solution-like products such as skin cosmetics.

At present, the concentration of phytosphingosine used in cosmetics is about 0.1 to 0.3% by weight, but it is difficult to obtain a desired effect sufficiently with such an amount. Phytosphingosine should be used in a minimum of 0.5% by weight or more in order to exhibit a sufficient effect, but it is thought that the optimum effect is exhibited when about 1 to 2% by weight is used. Consequently, in order to obtain optimal effects in cosmetic and pharmaceutical applications, methods must be developed that can dissolve phytosphingosine at high concentrations.

[0007]

Therefore, the inventors of the present invention have studied the above problems in detail, and as a result of long research, have found that water, lactic acid and willow bark extract can be used without using any solvent such as alcohol. The purpose is to dissolve phytosphingosine by at least 2% by weight and most by dissolving up to 10% by weight to obtain a clear solution-like aqueous solution of phytosphingosine.

[0008]

To achieve the above object, a step of adding phytosphingosine powder to distilled water at a predetermined concentration, heating the mixture to 60 to 90 ° C., and stirring if necessary, The method comprises the steps of adding a predetermined lactic acid or other acid and stirring to dissolve the phytosphingosine powder while adding them, and adding a predetermined willow bark extract to prevent recrystallization.

The high-concentration phytosphingosine aqueous solution produced by the method of the present invention is a high-concentration aqueous solution while having the functions of phytosphingosine such as antibacterial, anti-inflammatory and skin regeneration. Since phytosphingosine can be applied at a high concentration of up to 2% by weight, inconvenience in use is largely eliminated as compared with a conventional method in which phytosphingosine is separately dissolved and used using a solvent or the like.
In addition, since the commerciality has been greatly improved, it can be easily applied to water-soluble cosmetics such as skins, essences, water-soluble pack products, body essences, etc., which could not be used at all until now. Can also contribute significantly. Phytosphingosine in aqueous solution has the advantage that it is much more convenient to apply to existing cream products than to powder products, and can be easily applied to skin care cosmetics.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The present invention does not use any solvent such as isocetyl alcohol and uses water, lactic acid and willow bark extract (Willow Bark Extrac.
An object of the present invention is to provide a method for producing a phytosphingosine aqueous solution in a transparent state by completely dissolving phytosphingosine by at least 2% by weight and at most 10% by weight using t) or the like.

More specifically, phytosphingosine powder is added to distilled water at a concentration of 0.1% by weight to 10% by weight, more preferably at a concentration of 0.5% by weight to 6% by weight.
Stir for 30-40 minutes while raising the temperature to about 80 ° C. Then, while neutralizing the pH of the solution by gradually dropping lactic acid (Lactic Acid), the mixture is stirred for 30 to 40 minutes until phytosphingosine is completely dissolved. Lactic acid is preferably added in the range of 0.2 to 4 g per gram of phytosphingosine. As the phytosphingosine powder, phytosphingosine commercially available under the product name DS-phytosphingosine from Doosan Corporation was used as a raw material.

The dissolving temperature of phytosphingosine is 60 to
It is preferable to dissolve in the range of 90 ° C., and the dissolution time varies depending on the concentration of phytosphingosine,
Most preferably, it is dissolved with stirring for 50 minutes.
When phytosphingosine is completely dissolved, willow bark extract (WILLOW BARK EXTRACT, Brook Co., USA) containing about 10% by weight of salicylic acid, salicin, etc., is added to a solution of 0.1%.
When slowly added with stirring at a concentration of 10 to 10% by weight,
A transparent, high-concentration phytosphingosine aqueous solution can be obtained. As the willow bark aqueous solution used in the present invention, a Willow Bark extract sold by Brook Co., Ltd. of the United States was used.

Phytosphingosine is converted to lactic acid (Lactic Aci
In the case of dissolving using only an acid such as d), recrystallization proceeds with low-temperature storage and the passage of time. On the other hand, when phytosphingosine is dissolved using lactic acid and willow bark extract simultaneously. In spite of the low temperature storage and the long-term aging, it remained in an aqueous solution state or a transparent gel state without any change.

In order to obtain a transparent, liquid, high-concentration aqueous solution of phytosphingosine, phytosphingosine 0.5 to phytosphingosine is required.
In the range of 3% by weight, willow bark extract is 0.1 to 10% by weight.
Phytosphingosine is preferably added in an amount of 5 to 10% by weight, and willow bark extract in an amount of 2 to 10% by weight. If the willow bark extract is added to the aqueous solution of phytosphingosine at a concentration of 2% by weight or less, the phytosphingosine solution is recrystallized and cannot be used for products. When 10% by weight or more of willow bark extract is added, the viscosity of the phytosphingosine aqueous solution is greatly increased and the aqueous solution itself becomes hard, and the commerciality is reduced. Therefore, the present invention is applied to cosmetics such as cosmetic creams, skins, and water-soluble packs. For this purpose, there is a disadvantage that it must be used after being dissolved again.

[0015]

Example 1 Preparation of Phytosphingosine Aqueous Solution After adding 0.1% by weight of phytosphingosine powder to 100 ml of distilled water, the mixture was stirred at 70 rpm while the temperature was gradually raised to about 82 ° C. Lactic acid 0.2 with stirring
Dissolve phytosphingosine while adding g to neutralize the pH. After stirring for 30 minutes, it was visually confirmed that the phytosphingosine was completely dissolved, and then the stirring was continued and maintained, and 2% by weight of the willow bark extract was dropped, resulting in a slightly opaque hue and a slight viscosity. A phytosphingosine aqueous solution was obtained.

[0016]

Example 2 After adding 0.5% by weight of phytosphingosine powder to 100 ml of distilled water, the mixture was stirred at 80 rpm while the temperature was gradually raised to about 82 ° C. Phytosphingosine is dissolved while adding 0.5 g of lactic acid with stirring to neutralize the pH. After stirring for 30 minutes, it was visually confirmed that phytosphingosine was completely dissolved, and then 1% by weight of willow bark extract was gradually dropped while stirring, to produce a phytosphingosine aqueous solution in the form of a clear solution. Was.

[0017]

Example 3 After 5% by weight of phytosphingosine powder was added to 100 ml of distilled water, the mixture was stirred at 95 rpm while the temperature was gradually raised to about 80 ° C. Phytosphingosine is dissolved while adding 6 g of lactic acid with stirring to neutralize the pH. After stirring for 35 minutes, after visually confirming that phytosphingosine was completely dissolved,
When 2% by weight of willow bark extract was dropped with stirring,
A clear solution of phytosphingosine aqueous solution was produced.

[0018]

Test Example 1 Viscosity test of phytosphingosine aqueous solution 100 ml of distilled water was put into a 300 ml flask, and 0.1%, 0.5%, 1%, 3%, 5% and 6% by weight of phytosphingosine were added. %, 8% by weight, and 10% by weight, respectively, and then stirred while heating the temperature to about 80 ° C. Lactic acid is added to the mixture at a rate of 0.2 to 0.5 g per 1 g of phytosphingosine and stirred to dissolve phytosphingosine. After visually confirming that phytosphingosine was completely dissolved, 0.1% by weight, 0.5% by weight, 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight of willow bark extract was obtained. %, 10
The viscosity of the aqueous phytosphingosine solution was investigated while increasing the concentration of the solution by weight (Table 1).

The viscosity of the phytosphingosine aqueous solution increased as the concentrations of the phytosphingosine and willow bark extract increased to form a highly viscous gel, but 3-6% by weight of phytosphingosine and the willow bark extract The most stable phytosphingosine aqueous solution was maintained at a concentration of 0.1 to 3% by weight.

[0020]

Table 1 Changes in viscosity of phytosphingosine aqueous solution with increasing concentration of willow bark extract 1-2: no viscosity 3-4: low viscosity 5: high viscosity (gel state)

[0021]

Test Example 2 Transparency Experiment of Phytosphingosine Aqueous Solution As in Test Example 1, phytosphingosine was added in an amount of 0.1% by weight, 0.5% by weight, 1% by weight, 3% by weight, 5% by weight, and 6% by weight.
After being added to distilled water at a concentration of 8% by weight, 8% by weight, and 10% by weight, stirring is performed while heating the temperature to about 80 ° C. Lactic acid is added to the mixture at a rate of 0.2 to 0.5 g per 1 g of phytosphingosine and stirred to dissolve phytosphingosine. After visually confirming that the phytosphingosine was completely dissolved, 0.1% by weight, 0.5% by weight, 1% by weight, 2% by weight,
The phytosphingosine aqueous solution was examined for transparency while increasing the concentration to 4% by weight, 4% by weight, 5% by weight, and 10% by weight (Table 2).

Although there was a test device in which the transparency of the phytosphingosine aqueous solution increased and recrystallization occurred, 0.1 to 3% by weight of willow bark extract was added to 0.5 to 3% by weight of phytosphingosine. When 5 to 10% by weight of phytosphingosine and 2 to 10% by weight of willow bark extract were added, the liquid was maintained in a transparent liquid state.

[0023]

[Table 2] Change in transparency of phytosphingosine aqueous solution with increasing concentration of willow bark extract 1: transparent 3: somewhat opaque 5: opaque

[0024]

Test Example 3 Antibacterial Effect of Phytosphingosine Aqueous Solution After 100 ml of distilled water was added to a flask, phytosphingosine was added at a concentration of 5% by weight, and the temperature was reduced to about 8%.
Stir while heating to about 0 ° C. 2.8 g of lactic acid
While stirring slowly to dissolve phytosphingosine. After visually confirming that phytosphingosine was completely dissolved, a willow bark extract was added at a concentration of 1% by weight to obtain a transparent liquid phytosphingosine aqueous solution.

In order to measure the efficacy of the 5% by weight aqueous solution of phytosphingosine (containing 1% of willow bark extract), the microbial control effect was measured (see Tables 3 and 4 below). Test strains include Staphylococcus aureus, a kind of skin microorganism, and Propionibacterium echnis, the causative agent of acne.
bacterium acnes). After diluting the test strain with a buffer solution to give 3,000 to 4,000 cells per cc, phytosphingosine was added in 100 parts each.
After adding at a concentration of μg / cc, 10 μg / cc, 1 μg / cc, or 0.1 μg / cc, the mixture was incubated at 37 ° C. for 1 hour, spread on an agar medium and cultured for 24 hours, and the number of colonies was measured. .

In the comparative example, a 5% by weight aqueous solution of phytosphingosine to which willow bark extract was not added and phytosphingosine dissolved in alcohol were used.

[0027]

[Table 3] Phytosphingosine Staphylococcus aureu
Antibacterial effect on s (unit: number of villages) * Note) Comparative Example 1: 5% by weight aqueous solution of phytosphingosine (dissolved in cetyl alcohol) Comparative Example 2: 5% by weight aqueous solution of phytosphingosine (dissolved in lactic acid, without addition of willow bark extract) Comparative Example 3: Willow bark extract Invention: 5% by weight aqueous solution of phytosphingosine (1% by weight of willow bark extract added)

[0028]

[Table 4] Phytosphingosine Propionibacterium ac
Antibacterial effect on nes (unit: number of villages) * Note) Comparative Example 1: 5% by weight aqueous solution of phytosphingosine (dissolved in cetyl alcohol) Comparative Example 2: 5% by weight aqueous solution of phytosphingosine (dissolved in lactic acid, without addition of willow bark extract) Comparative Example 3: Willow bark extract Invention: 5% by weight aqueous solution of phytosphingosine (1% by weight of willow bark extract added)

As can be seen from Tables 3 and 4, the phytosphingosine aqueous solution according to the present invention is different from the comparative example.
Staphylococcus aureus, a skin microorganism
lococcus aureus) and Propionibacterium acnes, the causative agent of acne
Excellent antibacterial effect against etc.

[0030]

Test Example 4 Inhibitory effect of phytosphingosine-containing cosmetic cream on microorganisms resident on skin 5% by weight of phytosphingosine produced in Test Example 3
In order to observe the inhibitory effect of the aqueous solution (containing 1% by weight of willow bark extract) on microorganisms indigenous to the skin, a cosmetic cream containing phytosphingosine was manufactured and then smeared on the skin of the face to distribute the microorganisms indigenous to the skin. Changes were observed (see Table 5 below). 2.5g glyceride cream for cosmetics
2.5 g of cholesterol, 1.5 g of stearic acid, 3.5 g of ceramide, 1.5 g of oleic acid and 1.5% of hydrated lecithin were completely dissolved therein, and 100 ml of a 5% aqueous solution of phytosphingosine was added thereto. A cosmetic cream was produced. Two hours after the cosmetic cream was applied to one face of nine subjects, the microbial distribution on both sides of the face was examined.

[0031]

[Table 5] Inhibitory effect of phytosphingosine cosmetic cream on microorganisms resident on skin (unit: number of villages)

As can be seen from Table 5, the skin of the test subjects to which the aqueous solution of phytosphingosine according to the present invention was applied significantly reduced the microorganisms indigenous to the skin as compared with the area where no cream was applied.

[0033]

As described above, the high-concentration aqueous solution of phytosphingosine produced by the method of the present invention has the functions of phytosphingosine such as antibacterial, anti-inflammatory, and skin regeneration, and has a high-concentration aqueous solution. Therefore, it can be used in various cosmetics at a high concentration of 1 to 2% by weight, so that inconvenience in use can be largely eliminated as compared with a conventional method in which phytosphingosine is separately dissolved and used with a solvent or the like. Further, it can be easily applied to water-soluble cosmetics such as skin, essence, water-soluble pack product, body essence, etc., which could not be applied at all up to the present, and can greatly contribute to the improvement of the functions of water-soluble cosmetics. Phytosphingosine in aqueous solution has the advantage that it is much more convenient to apply to existing cream products than to powder products and can be easily applied to skin care cosmetics.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 7/00 A61K 7/00 Y 7/48 7/48 A61P 31/04 A61P 31/04 C07C 215/24 C07C 215/24 ( 72) Inventor Chong Ji Hong Kyunggi Suwonsi Paldaluk Methane 2don 1216-1 Taedonvilla 102don 30e (56) References JP-A-2000-191496 (JP, A) JP-A-2000-256188 (JP, A) European Patent Application Publication 2791260 (EP, A1) US Pat. No. 5,616,332 (US, A) French Patent Application Publication No. 2779059 (FR, A1) International Publication No. 95/3028 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB) Name) C07C 213/08 A61K 7/00 A61K 7/48 A61P 31/04 C07C 215/24 CAPLUS (STN)

Claims (8)

(57) [Claims] 1. A phytosphingosine powder is added to distilled water in a volume of 0.
Adding at a concentration of 1% by weight to 10% by weight, heating to 60 to 90 ° C., and stirring if necessary; adding predetermined lactic acid to dissolve the phytosphingosine powder while neutralizing the pH Phytosphingosine powder to prevent recrystallization.
Adding a willow bark extract having a concentration of 0.2% by weight to 10% by weight depending on the concentration of the phytosphingosine aqueous solution. 2. The method for producing an aqueous phytosphingosine solution according to claim 1, wherein said lactic acid is added in an amount of 0.2 g to 4 g per 1 g of phytosphingosine. 3. The willow bark extract added to prevent recrystallization is composed of about 10 parts of salicylic acid and salicin.
2. The method for producing an aqueous solution of phytosphingosine according to claim 1, wherein a willow bark extract containing about% by weight is used. 4. Phytosphingosine powder added to distilled water
A powder having a concentration of 0.5% by weight to 6% by weight.
Preparation of the phytosphingosine aqueous solution according to any one of the above items.
Construction method. 5. The production method according to claim 1, wherein:
Phytosphingosine aqueous solution produced by the method. 6. A method for using an aqueous solution of phytosphingosine, which comprises using the aqueous solution of phytosphingosine according to claim 5 for cosmetics such as cosmetic creams, essences, water-soluble packs, skins, and body essences. 7. The method for using a phytosphingosine aqueous solution according to claim 6, wherein the aqueous solution of phytosphingosine added to the cosmetic is used in an amount of 0.1% by weight to 10% by weight. 8. The method according to claim 7, wherein the aqueous phytosphingosine solution is used in cosmetics at a concentration of 0.1% by weight to 5% by weight.