JP5689247B2 - Ceramide production promoter and moisturizer - Google Patents

Description

  The present invention relates to a ceramide production promoter and a humectant.

Ceramide, one of the sphingolipids, is a very small amount of lipid in the whole body, but in the stratum corneum, which is the outermost layer of the skin, it occupies more than half of the lipid, and is a moisturizing and barrier mechanism for the skin. Plays an important role. This ceramide functions by constructing a lamellar structure between cells in the stratum corneum after being produced and secreted in epidermal cells. However, in skin diseases such as dry skin, rough skin, atopic dermatitis, senile psoriasis and psoriasis, the healthy metabolism of ceramide is hindered, and the amount of ceramide in the stratum corneum is reduced, resulting in skin moisturizing ability and It has been reported a lot that the barrier ability is lowered.
Attempts have been made to replenish the reduced ceramide from the outside, but the effect is not always sufficient at present.

  An object of the present invention is to provide a ceramide production promoter having a high ceramide production promotion effect. Moreover, this invention makes it a subject to provide the moisturizer excellent in the effect | action which accelerates | stimulates ceramide production.

  In view of the above-mentioned problems, the present inventors have intensively studied to search for a new material having a ceramide production promoting action. As a result, it was found that the compound represented by the following general formula (1) has a high ceramide production promoting action, and the knowledge that the compound is useful as a novel moisturizing component was obtained. The present invention has been made based on this finding.

  That is, this invention relates to the ceramide production promoter which contains the compound represented by following General formula (1) as an active ingredient.

（式中、Ｒは炭素数１〜５のアシル基を表す。）

(In the formula, R represents an acyl group having 1 to 5 carbon atoms.)

  The present invention also relates to a humectant containing the compound represented by the general formula (1) as an active ingredient.

  According to the present invention, a ceramide production promoter can be provided. Moreover, according to this invention, the moisturizing agent excellent in the ceramide production promotion effect can be provided.

Hereinafter, the present invention will be described in detail.
The ceramide production promoter and humectant of the present invention contain a compound represented by the following general formula (1) as an active ingredient. As demonstrated in Examples described later, this compound has a high ceramide production promoting action.

In general formula (1), R represents an acyl group having 1 to 5 carbon atoms.
R is preferably an acyl group having 1 to 3 carbon atoms, and more preferably an acyl group having 2 carbon atoms. Specific examples of R include formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, and the like. Formyl group, acetyl group, and propionyl group are preferable, and acetyl group is more preferable. The compound represented by the general formula (1) in which R is an acetyl group is one type of terpene, Toosendanin.
The compound represented by the general formula (1) can have the following tautomerism, but the compound represented by the general formula (1) of the present invention includes both tautomers thereof.

The method for producing the compound represented by the general formula (1) used in the present invention is not particularly limited, and a chemically synthesized product may be used, which may be extracted or purified from a natural product-derived material. May be. Moreover, what is marketed as a reagent can also be used.
As the reagent, those commercially available from AvaChem (USA) can be used.

Examples of a method for obtaining the compound represented by the general formula (1) from a natural product-derived material include Towsendan (scientific name: Melia toosendan Sieb. Et Zucc.), Sendan (scientific name: Melia azedarach ), and Chanchin (scientific name: It can be isolated from plants such as Toona sinensis ).
These plants can be used in any arbitrary part (whole tree, whole grass, root, rhizome, stem, branch, stem, leaf, bark, sap, resin, flower, fruit, seed, etc.). is there. In particular, when it is isolated from towsendan, it is preferable to use its bark, seed or fruit. In addition, a herbal medicine, Senrenshi, obtained from the fruit of towsendan as a base plant can also be used. When isolated from Sendang, it is preferable to use the bark. It is also possible to use herbal medicine, krempi, obtained by using the bark of Sendang as a base plant. When isolated from chanchin, it is preferable to use the bark.
Moreover, the compound represented by the said General formula (1) can also be isolated using combining each plant or each site | part suitably.

A method for isolating the compound represented by the general formula (1) from these plants is not particularly limited. For example, the plant extract obtained by extracting the above-described plant using an appropriate solvent is obtained. And a method of isolating the compound represented by the general formula (1) by a technique such as chromatography.
For the preparation of the plant extract, the above plant may be used as it is, or dried and ground. Solvents used for extraction are those usually used for extraction of plant components, such as water, petroleum ether, n-hexane, toluene, chloroform, ether, ethyl acetate, acetone, methanol, ethanol, propanol, butanol, ethylene glycol, propylene. Glycol, butylene glycol, and a mixed solution thereof can be used. Moreover, normal conditions can be applied as extraction conditions. For example, the above-described plant may be immersed or heated to reflux at 5 to 80 ° C. for 2 hours to 60 days.
As specific extraction and isolation methods, the methods shown in the Examples described later can be used, but the present invention is not limited thereto.

  The compound represented by the general formula (1) has an excellent ceramide production promoting action as shown in Examples described later, and a ceramide production promoter can be obtained by containing this compound. In addition, as described above, ceramide plays an important role for the skin moisturizing mechanism and barrier mechanism. By promoting ceramide production, the ceramide production mechanism of the living body is restored to normal and the ceramide in the stratum corneum is reduced. Since the skin having high barrier function and moisturizing function can be recovered, the moisturizing agent can be obtained by containing the compound represented by the general formula (1). It has never been known that the compound represented by the general formula (1) has a ceramide production promoting action, which is a new finding obtained by the present inventors.

In the present invention, the compound represented by the general formula (1) may be used as it is as a ceramide production promoter. Or you may add various additives etc. to the compound represented by the said General formula (1) in the range which does not affect the effect. For example, an appropriate liquid or solid excipient or filler such as titanium oxide, calcium carbonate, distilled water, lactose, starch, etc. may be added and used as a ceramide production promoter.
When the composition is used, the amount of the compound represented by the general formula (1) in the ceramide production promoter is not particularly limited, but the compound represented by the general formula (1) is 0.00001 to 20% by mass. It is preferably contained, and particularly preferably about 0.0001 to 10% by mass.

In the present invention, the compound represented by the general formula (1) may be used as it is as a humectant. Alternatively, the compound represented by the general formula (1) is contained as an active ingredient, and additives that are usually used, other medicinal ingredients, etc. are blended to make a moisturizer as long as the effect is not affected. You can also. For example, a known ceramide production promoter, pseudoceramide, natural ceramide, sugar ceramide and the like may be added together. Furthermore, you may add skin antiaging agent, a whitening agent, etc. together as medicinal components other than a moisturizer.
The ceramide production promoter is not particularly limited. For example, acetylhydroxyproline, potassium glycyrrhizinate, L-carnitine, ascorbic acid, ascorbyl glucoside, magnesium ascorbyl phosphate, dl-α-tocopheryl-dl- Ascorbyl phosphate, dl-α-tocopheryl phosphate, nicotinamide, tocopherol nicotinate, L-lactic acid, vitamin C, asparagus extract, butcher bloom, genquanine, rosemary, lavender, sage, jujube, black (red ) Ganoderma, Toki, Kujin, Yokuinin, Beniceanne extract, Rice power extract, etc.
The pseudo ceramide is not particularly limited. For example, commercially available ceramide R (manufactured by Unilever), ceramide PC-104 (manufactured by Taiheiyo Chemical), ceramide HO3 (manufactured by sederma), Erduo PS-203 (Ajinomoto) Manufactured).
The sugar ceramide is not particularly limited, and examples thereof include glucosyl ceramide, galactosyl ceramide, etc., and commercially available nip ceramide (manufactured by Nippon Flour), oryzah ceramide (manufactured by Oriza Yoka), Nissan Examples include ceramide, neo-liquid ceramide N (manufactured by NOF Corporation), ceramide (manufactured by Unitika) and the like.
In the case of a composition, the amount of the compound represented by the general formula (1) in the moisturizing agent is not particularly limited, but 0.00001 to 20% by mass of the compound represented by the general formula (1) is included. Is more preferable, and 0.0001 to 10% by mass is more preferable.

  Most of the humectants of the present invention are applied to humans and animals. This humectant includes all forms that can be applied to human and animal skin, nails, mucous membranes, hair and the like. Examples of the moisturizing agent of the present invention include ointments, lotions, creams, serums, lotions, massage agents, packs, foundations, lipsticks, bathing agents, shampoos, hair conditioners, hair tonics, tablets, capsules, sanitary products. Absorbent articles such as wiping cloths, sheet-like products such as wet tissues, and the like. The dosage form is not limited, and examples thereof include various dosage forms such as liquid, solid, emulsion, paste, gel, powder (powder), granule, pellet, and stick.

The ceramide production promoter and humectant of the present invention can be applied to uses such as foods, cosmetics, and pharmaceuticals.
When used in food applications, in addition to general food and drink, the concept is the effect of improving and maintaining the skin's moisturizing ability or barrier function. It can be used as a food or drink for the sick.
There is no particular limitation on the form of the food, for example, beverages such as fruit juice beverages, milk beverages, tea beverages, confectionery such as candy, drop, jelly, cookies, chocolate, cakes, yogurt, gum, seasonings, cooking Examples include oil, dairy products, breads, noodles, and processed rice. Moreover, it is good also as beauty foods, health foods, etc., such as a tablet (tablet), a capsule, a granule, and a syrup.
For these beverages or foods, for example, additives such as sweeteners, colorants, antioxidants, vitamins, fragrances, minerals, etc., and food ingredients such as proteins, lipids, carbohydrates, carbohydrates, dietary fibers, etc. are used in appropriate combinations. It can be prepared by incorporating the compound represented by the general formula (1) into various food forms according to a conventional method.

When used for cosmetics, for example, it can be in the form of an external preparation for skin. When used in the form of an external preparation for skin, in addition to the compound represented by the general formula (1), the above-mentioned various additives and other medicinal components can be appropriately added, and further, depending on the dosage form that can be taken. Various components that are usually used in external preparations for skin can be blended. Specific examples of dosage forms for external preparations for skin include various dosage forms that can be applied externally, such as creams, emulsions, lotions, gels, ointments, pastes, packs, sheet-like products, and the like. For example, various oil agents, surfactants, gelling agents, preservatives, antioxidants, solvents, alcohol, water, chelating agents, thickeners, ultraviolet absorbers, emulsion stabilizers, pH adjusters, dyes, and fragrances Etc. can be blended.
The content of the compound represented by the general formula (1) in the external preparation for skin is the same as the amount of the compound represented by the general formula (1) in the ceramide production promoter and moisturizer described above.

  Ingestion or use amount of the ceramide production promoter or moisturizer of the present invention as food, cosmetics or pharmaceuticals can be appropriately selected depending on the form, age of the consumer, sex, etc. It is preferable to ingest or use 0.001 to 1000 mg, particularly preferably 0.01 to 100 mg of the compound represented by the general formula (1) per day per person.

  EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is not limited to this.

Production Example 800 g of tousendan fruit (Senrenshi, manufactured by Shinwa Bussan Co., Ltd.) was extracted with 8 L of 50% ethanol at 20 to 35 ° C. for 7 days, and the solvent was concentrated to obtain 123.5 g of an extracted solid content. The obtained extracted solid content was fractionated using as an index ceramide production promoting activity by the method of the test example described later. When liquid-liquid partition was performed using water and ethyl acetate, the activity was concentrated in 20.78 g (yield 16.8%) of the ethyl acetate layer. The ethyl acetate layer was further fractionated with a silica gel column to obtain 7.49 g (yield 6.1%) of fraction (1). Further, this fraction was fractionated using a silica gel column to obtain 2.78 g of fraction (2) (yield 2.3%). Next, this fraction was fractionated by LH-20 (manufactured by GE Healthcare: Sephadex ^™ LH20) to obtain 1.28 g (1.0% yield) of fraction (3). Of these, 340 mg was fractionated by HPLC to obtain 164.8 mg (yield 0.48%) of fraction (4). Furthermore, when fractionation was performed by HPLC using 20 mg of this, 1.4 mg (yield 0.03%) of fraction (5) was obtained. This fraction (5) was subjected to structural analysis using NMR. In addition, in the structural analysis by NMR, commercially available towsendanine (manufactured by AvaChem) was used for comparison. The results of structural analysis by NMR are shown in Table 1.
As a result, the active ingredient isolated from towsendan was a compound having the structure shown in Table 1 below, and this compound was identified as tosendanin. In Table 1, Ac represents an acetyl group.

(Test example) Verification of ceramide production promoting effect Normal human epidermal keratinocytes (trade name: NHEK (F), KURABO) in culture solution (trade name: EpiLife-KG2, manufactured by KURABO) using a culture plate Manufactured at 37 ° C. and 5% CO ₂ .
Thereafter, the culture solution was replaced with EpiLife-KG2 from which growth factors such as epidermal growth factor were removed, and a control solution (50% ethanol) prepared such that the concentration of towsendanine (manufactured by AvaChem) was 1 mM (574 ppm). Was added in an amount of 0.01%.
After culturing for 3 days, each cell was collected together with 1 well.

The organic phase from which the lipid was extracted from the collected cells by the Bligh and Dyer method was transferred to a glass tube, solidified with nitrogen, and then redissolved with chloroform and methanol to obtain a lipid sample.
In addition, 0.1N NaOH, 1% SDS aqueous solution is added to the cells after lipid extraction, and the protein is solubilized by heating at 60 ° C. for 2 hours, cooled to room temperature, and then neutralized by adding 2N HCl. The amount of protein was quantified by the BCA method.

The prepared lipid sample was horizontally developed by thin film chromatography (TLC) twice with chloroform: methanol: acetic acid = 190: 9: 1. The copper sulfate solution was sprayed and sprayed with a hot plate to detect ceramide, and the amount was determined.
The results are shown in Table 2. The amount of ceramide shown in Table 2 indicates a relative value when the control solution addition group is 1.

(Reference example)
1. Preparation of Eucalyptus Extract 40 g of Eucalyptus globulus Labillardiere (manufactured by Shinwa Bussan Co., Ltd.) was chopped, 400 mL of 50% ethanol was added, and extraction was performed for 7 days under room temperature and standing conditions. Then, it filtered and 291 mL of eucalyptus extracts were obtained. About the obtained extract, when the evaporation residue was computed by the following method, the evaporation residue was 3.16% (w / v).

2. Verification of ceramide production promoting effect Using the obtained eucalyptus extract, the ceramide production promoting effect was verified by the same method as in the above test example. In addition, 0.001% of the extract adjusted so that a density | concentration might be 1% (w / v) in conversion of solid content added to the cell.
The results are shown in Table 2. Eucalyptus extract is known as a moisturizing ingredient having a ceramide production promoting action.

As is apparent from Table 2, the ceramide output of the present invention containing the compound represented by the general formula (1) as an active ingredient was observed in the system added with towsendanine as compared with the control system. It was found that production promoters can promote ceramide production.
Furthermore, since ceramide is related to the moisture retention / barrier function maintenance of the skin, it can be seen from the results in Table 2 that the compound represented by the general formula (1) promotes the production of ceramide and has a moisturizing action. That is, like the eucalyptus extract (reference example), which is a known moisturizing component, the moisturizing agent of the present invention containing the compound represented by the general formula (1) as an active ingredient promotes the production of ceramide and has a moisturizing action. I have it.

(Prescription example)
A skin lotion, a 0 / W (oil-in-water) type emulsion, a W / O (water-in-oil) type cream, and a gel-like cosmetic having the following composition, with the compound represented by the general formula (1) as an active ingredient The liquid bath preparation and the food in the form of tablets were prepared by conventional methods.

1. Preparation of lotion (composition) (formulation: mass%)
Towsendanine (AvaChem) 0.05
Polyethylene glycol (trade name: PEG-1540, manufactured by Sanyo Chemical Co., Ltd.) 1.00
Polyoxyethylene (20) sorbitan monolaurate 1.50
Glycerin 2.00
Paraben 0.10
Purified water residue

2. Preparation of 0 / W emulsion (composition) (formulation: mass%)
Tousendanin (AvaChem) 1.00
Polyethylene glycol (trade name: PEG-2000, manufactured by Sanyo Chemical Co., Ltd.) 1.00
Pullulan (trade name: Pullulan PT-20, manufactured by Hayashibara) 0.40
Cetyl alcohol 1.00
Vaseline 2.00
Squalane 6.00
Dimethylpolysiloxane 2.00
Glycerin 2.00
Pseudoceramide (N- (3-hexadecyloxy-2-hydroxypropyl) -N-2-hydroxyethylhexadecaminad) 1.00
Polyoxyethylene (10) monooleate 1.00
Glycerol monostearate 1.00
Acid heteropolysaccharide derived from plant callus (1% by weight aqueous solution of tuberose polysaccharide) 2.00
Paraben 0.20
Purified water residue

3. Preparation (composition) of W / O type cream (Formulation: mass%)
Tousendanin (AvaChem) 3.00
Alkyl acrylate copolymer (trade name: Yodosol GH810, manufactured by Kanebo NSC)
1.30
Polyvinylpyrrolidone (Brand name: Rubiscol K-90, manufactured by BASE Japan)
0.70
Dimethylpolysiloxane 10.00
Methylphenylpolysiloxane 3.00
Octamethylcyclotetrasiloxane 12.00
Polyoxyalkylene modified silicone 5.00
1,3-butylene glycol 6.00
Pseudoceramide (N- (3-hexadecyloxy-2-hydroxypropyl) -N-2-hydroxyethylhexadecaminad) 1.20
Paraben 0.20
Perfume Trace amount Purified water Residual

4). Preparation (composition) of gel cosmetic (formulation: mass%)
Tousendanin (AvaChem) 0.50
Polyethylene glycol (trade name: PEG-2000, manufactured by Sanyo Chemical Co., Ltd.) 0.50
Xanthan gum (trade name: Neosoft XKK, manufactured by Kojinsha) 0.20
Glycerin 3.00
Ethanol 3.00
Carboxyvinyl polymer 0.50
Potassium hydroxide 0.15
Polyoxyethylene hydrogenated castor oil 1.00
Citric acid 0.80
Trisodium citrate 0.80
Nylon powder 1.00
Paraben 0.10
Perfume Trace amount Purified water Residual

5. Preparation of liquid bathing agent (composition) (formulation: mass%)
Towsendanine (AvaChem) 0.01
Pseudoceramide (N- (3-hexadecyloxy-2-hydroxypropyl) -N-2-hydroxyethylhexadecaminad) 0.10
Isopropyl myristate 15.00
Polyoxyethylene (12) oleyl ether 10.00
Polyoxyethylene (6) oleyl ether 6.00
Acid heteropolysaccharide derived from plant callus (1% by weight aqueous solution of tuberose polysaccharide) 2.00
Paraben 0.30
Perfume Trace amount Liquid paraffin Residue

6). Preparation of food Each material was mixed according to the following composition and formed into a tablet.
(Composition) (Composition: Mass%)
Tousendanin (AvaChem) 1.0
Crystalline cellulose 89.0
Whey calcium residue

Claims (2)

Ceramide production promoter shall be the active ingredient a compound represented by the following general formula (1).

(In the formula, R represents an acyl group having 1 to 5 carbon atoms.) Humectant you as an active ingredient a compound represented by the following general formula (1).

(In the formula, R represents an acyl group having 1 to 5 carbon atoms.)