KR101433913B1 - Glycosyl ceramide compound, and composition comprising the compound - Google Patents

Abstract

As the glycosyl ceramide represented by the following formula 1, compounds having the use of improving skin barrier function, improving skin elasticity, repairing damaged skin, moisturizing skin, improving skin wrinkles, preventing skin aging, improving hair condition, do.
[Chemical Formula 1]

Description

[0001] Glycosyl ceramide compounds and compositions containing them [0002]

TECHNICAL FIELD The present invention relates to a derivative having excellent physiological activity with ceramide as a basic skeleton.

Ceramide is one of the constituents of the skin, the sphingolipid, which is represented by Sphingomyelin and glycoshingolipid, which is composed of 18 carbons, a sphingoid long base It refers to a complex lipid having a structure in which various polar head groups are modified with C1-OH of a ceramide in which a fatty acid is amide bonded to a 2-amino group.

It was found that there are seven kinds of ceramides present in the skin. In the role, the keratinocytes in the outer skin of the human skin are bonded to the skin surface by the double chain lamellar structure of the ceramide which exists in the stratum corneum in abundance and maintains smooth and elastic skin do. However, as the skin ages with age, the amount of ceramide in the stratum corneum decreases, which decreases the binding force of keratinocytes to the skin surface, and the stratum corneum is not protected. That is, as the content of ceramides in the stratum corneum decreases, the skin surface becomes rough due to loss of skin moisture, exposure to external stimuli such as ultraviolet rays or chemicals, and exfoliation of keratinocytes. However, a signal transduction process called the Sphingomyelin Cycle creates ceramides that can restore the skin to normal conditions. In order to supplement ceramides from the outside, searches for natural flora and fauna have been carried out, and a variety of flora and fauna and microorganisms containing ceramides have been revealed. However, ceramides present in these plants, animals and microorganisms are extremely small in quantity, and it takes a lot of production cost to extract them. In addition to these problems, natural-derived ceramides have very low solubility in various solvents, cosmetics, raw materials used in cleaning products, etc., and thus only a small amount of natural ceramide can be used in the production of these products. There are disadvantages. In addition, the stereochemical structure was different from the sphingolipid existing in the human body. In order to overcome such disadvantages, pseudo-ceramide has been recently developed through organic synthesis based on the structural features of ceramide. Korean Patent Laid-Open Publication No. 2004-0021724 discloses a novel pseudoceramide. Saturated and unsaturated Pseudoceramides having straight chain and branched aliphatic hydrocarbon groups and a preparation method thereof are disclosed.

Korean Patent Publication No. 2004-0021724

The present invention provides a novel glycosyl ceramide having a shape similar to that of a ceramide present in the human body by condensing a sugar and a ceramide. It is intended to provide a novel glycosyl ceramide having a regenerating effect on the skin cells which has the same or more superior effect as the existing glycosyl ceramide and is also capable of mass production and utilization.

In order to achieve the above object, a glycosyl ceramide according to an embodiment of the present invention is a glycosyl ceramide compound represented by the following general formula (1).

[Chemical Formula 1]

In this formula,

n is an integer of 1 to 4,

m is an integer of 1 to 4,

R ₁ , R ₂ and R ₃ are each independently hydrogen or the same or different glycosyl group, and at least one of R ₁ , R ₂ and R ₃ is a glycosyl group

R ₄ and R ₅ are an alkyl group having 1 to 20 carbon atoms or an alkenyl group.

The glycosyl ceramide according to another embodiment of the present invention is a glycosyl ceramide of formula (2a) or (2b), which has excellent physiological activity effect using ceramide as a basic skeleton which is a compound of formula (3a) or (3b).

(2a)

(2b)

[Chemical Formula 3]

(3b)

 [Chemical Formula 4]

The novel compound according to one embodiment of the present invention is a glycosyl ceramide compound of the following formula (2a) or (2b).

(2a)

(2b)

The method for preparing glycosyl ceramide according to an embodiment of the present invention may include reacting a compound of formula (3a) or (3b) with diacetal galactose.

[Chemical Formula 3]

(3b)

The compound in which the compound of the above formula (3a) or (3b) is coupled with diacetal galactose may be the following compound:

[Chemical Formula 5a]

[Chemical Formula 5b]

The cosmetic composition according to one embodiment of the present invention comprises the compound of formula (I) as an active ingredient.

In the cosmetic composition according to an embodiment of the present invention, the composition may contain 0.001% to 80% by weight of the compound of formula (1).

The cosmetic composition according to one embodiment of the present invention may be used for improving skin barrier function, improving skin elasticity, repairing damaged skin, moisturizing skin, improving wrinkles of skin, preventing aging of skin, improving hair condition or alleviating atopic skin have.

The pharmaceutical composition according to one embodiment of the present invention may contain the compound of the formula (1) as an active ingredient.

The medicinal composition according to one embodiment of the present invention may contain 0.001% to 80% by weight of the compound of formula (1).

The medicinal composition according to one embodiment of the present invention may have a use for prevention, improvement or treatment of a skin disease.

In the pharmaceutical composition according to an embodiment of the present invention, the skin disease may be atopic dermatosis or atopic skin symptom.

The glycosyl ceramide represented by the formula (1) has an effect of increasing the elasticity of the skin by increasing the activity of the skin surface layer, restoring the damaged skin barrier function, and especially effective for atopic dermatitis. Glycosyl ceramide is a medicinal ingredient that stimulates ceramide replenishment and cell differentiation in various skin diseases, and can be used cosmetically and medically. In addition, it can show the effect of moisturizing skin, improving skin wrinkles and preventing skin aging.

Fig. 1A shows data of diacetal galactosyl ceramide 3B. 1B is NMR data of galactosyl ceramide 3, and FIG. 1C is NMR data of galactosyl ceramide 3B.
Fig. 2 shows the regeneration effect of the skin after damaging the skin surface layer. FIG. 2 (a) is a photograph showing a skin in which a lipid layer has disappeared in a skin layer, FIG. 2 (b) a control group, and FIG. 2 (c) photographs after treating 0.3% galactosylceramide.
3 is a graph showing the effect of galactosyl ceramide on the moisture evaporation rate of damaged skin.
4 is a photograph showing the protective effect of the hair.

The glycosyl ceramide compounds disclosed in the present specification can be represented by the following formula (1).

[Chemical Formula 1]

In this formula,

n is an integer of 1 to 4,

m is an integer of 1 to 4,

R ₁ , R ₂ and R ₃ are each independently hydrogen or the same or different glycosyl group, at least one of R ₁ , R ₂ and R ₃ is a glycosyl group,

R ₄ and R ₅ are an alkyl group having 1 to 20 carbon atoms or an alkenyl group.

In the present invention, the glycosyl group is not particularly limited as long as it is a monosaccharide. However, the glycosyl group is preferably selected from the group consisting of galactose, ribose, arabinose, xylose, ribulose, glucose, fructose, mannose, glyceraldehyde, dihydroxyacetone, It may be at least one selected from the group consisting of erythrose, erythrose, threose, xylulose, tagatose, sorbose, rhamnose, ricosource, aloose, altrose, gulose, idose and talose.

In another embodiment, the glycosyl group can be a hexadecyl group. In another embodiment, the glycosyl group may be galactose.

In one embodiment, the glycosyl group may be bonded to the ceramide at the 6 carbon position of the saccharide saccharide. The carbon position of the 6th carbon atom of the saccharide is galactose, for example, as follows.

In one embodiment, R ₄ is an alkyl or alkenyl group having 17 carbon atoms, and R ₅ may be an alkyl group having 14 carbon atoms. Also, R ₁ may be galactose and R ₂ and R ₃ may be hydrogen.

In the present specification, the glycosyl ceramide is a monosaccharide such as pentose or hexose bonded to ceramide. For example, the sugar bound to ceramides includes all pentoses and hexoses such as glucose, glucopyranose, galactose, galactopyranose, fructose, fructofuranose, and the like. In particular, it may be a ceramide having galactopyranose bound thereto.

The compound of formula (1) can be prepared, for example, by using a coupling reagent in the presence of a catalyst, in a solvent, a ceramide and a galactose of the following formulas (3a) and (3b). The galactose used in the above step can be produced by transforming into a structure that is easy to bind with N-Acyl phytosphingosine C18 or N-Acyl phytosphingosine C18: 1 over two steps.

The manufacturing method will be described in more detail as follows.

The compound of Formula 1 is prepared by reacting ceramide 3 (N-Acyl phytosphingosine C18), a compound of Formula 3a, and N-Acyl phytosphingosine C18: 1, a compound of Formula 3b in the presence of a condensing agent and an organic amine catalyst, Of galactose. Triethylamine or pyridine is preferably used as the organic amine serving as a catalyst, and the amount of the organic amine is preferably 1.0 to 1.5 mol based on the compound of formula (IV). As the condensation agent, p-toluenesulfonyl chloride, methanesulfonyl chloride or mesyl chloride is used, and the reaction is carried out at room temperature.

       However, the catalyst and the condensing agent which can be used in the process according to the present invention are not limited to those listed above, and all those conventionally known in the art can be used as long as they do not affect the reaction. The compounds of formula (2a) and (2b) prepared by the above-described method can be purified by conventional separation and purification methods such as recrystallization or extraction.

The transformation of the diacetal galactosyl ceramide into galactosyl ceramide can be carried out using an organic acid or an inorganic acid such as hydrochloric acid or sulfuric acid. The amount of these added can be 1 to 50% based on the total weight of the diacetal galactosylceramide.

The pharmaceutically acceptable carrier to be contained in the pharmaceutical composition of the present invention may be any of those conventionally used in the formulation. For example, it is possible to use a water-soluble polymer such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, But are not limited to, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components.

The pharmaceutical composition of the present invention may be administered in various ways, but transdermal administration is most preferred. In particular, it is applied locally to the skin.

The appropriate dosage of the pharmaceutical composition of the present invention varies depending on factors such as the formulation method, administration method, age, body weight, sex, severity of disease symptoms, food, administration time, administration route, excretion rate and responsiveness of the patient And the ordinarily skilled physician can easily determine and prescribe dosages effective for the desired treatment. Preferably, the daily dosage of the pharmaceutical composition of the present invention is about 0.001-100 mg / kg.

The pharmaceutical composition of the present invention may be formulated into a unit dosage form by using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.

The content of the glycosyl ceramide compound as an active ingredient in the pharmaceutical composition of the present invention may be 0.0001-80.0 wt% with respect to the total composition. Preferably 0.0005 to 40.0% by weight, and more preferably 0.01 to 20% by weight. Still more preferably from 0.1 to 10% by weight. If the content is too low, the effect is insignificant; if too high, the formulation stability is poor.

According to another aspect of the present invention, the present invention provides a functional cosmetic composition.

The content of the glycosyl ceramide compound as an active ingredient in the cosmetic composition of the present invention may be from 0.0001 to 80.0% by weight based on the total cosmetic composition. Preferably 0.0005 to 40.0% by weight, and more preferably 0.01 to 20% by weight. Still more preferably from 0.1 to 10% by weight. If the content is too low, the effect is insignificant; if too high, the formulation stability is poor.

The ingredients contained in the cosmetic composition of the present invention include components commonly used in cosmetic compositions in addition to pseudoceramide compounds as active ingredients and include conventional adjuvants such as antioxidants, stabilizers, solubilizers, vitamins, And a carrier.

The cosmetic composition of the present invention can be prepared into any of the formulations conventionally produced in the art and can be used as a solution, a suspension, an emulsion, a paste, a gel, a cream, a lotion, a powder, a soap, , Oil, powder foundation, emulsion foundation, wax foundation and spray, but is not limited thereto. More specifically, it can be manufactured in the form of a soft lotion, a nutritional lotion, a nutritional cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray or a powder.

When the formulation of the present invention is a paste, cream or gel, an animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier component .

When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In the case of a spray, in particular, / Propane or dimethyl ether.

When the formulation of the present invention is a solution or an emulsion, a solvent, a dissolving agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.

In the case where the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.

When the formulation of the present invention is an interfacial active agent-containing cleansing, the carrier component may include aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters.

Hereinafter, the present invention will be described more specifically based on the following examples and experimental examples. It should be understood, however, that these examples and experimental examples are provided only to facilitate understanding of the present invention, and the scope of the present invention is not limited to these examples in any sense.

[Example 1: Preparation of diacetal galactose]

100 g of galactosyl was placed in a round three-necked flask, and 150 g of ZnCl 2, 5 g of sulfuric acid, and 1000 ml of acetone were placed in a round three-necked flask. While reacting at room temperature for 4 hours, galactosyl form of acetonide was obtained. The yield of the diacetal galactose was 110 g (95.8%).

[Example 2: Binding of diacetal galactose to ceramide 3 and ceramide 3B]

After dissolving 36 g (0.140 mol) of diacetal galactose in 1000 ml of anhydrous methylene chloride, 30 g (0.154 mol) of methanesulfonyl chloride and 15 g (0.154 mol) of triethylamine were added and the mixture was stirred at room temperature for 1 hour. 80 g (0.140 mol) of ceramide 3 and 3B were added to the reaction mixture, and after 4 hours, the mixture was extracted with water and washed. The separated organic layer was concentrated by distillation under reduced pressure. 10% hydrochloric acid aqueous solution was added to remove the diacetal group And recrystallized in 1000 ml of methanol for 2 hours at -4 ° C to remove remaining diacetal galactose and unreacted ceramide. The precipitate was filtered and dried to obtain 80 g (yield 76%) of the title compound as white. Fig. 1B is NMR data of the obtained galactosyl ceramide 3, and Fig. 1C is NMR data of the obtained galactosyl ceramide 3B.

[Experimental Example 1: Restoration Effect of Damaged Skin Barrier 1]

In order to investigate the restoration effect of galactosyl ceramide on skin barrier, the following experiment was conducted. First, the amount of water evaporation on both sides was measured using a TEWL instrument (TEWAMETER, TM210, Germany) using 10 reared undiluted mice (Sumataka Bio Korea, Korea) at 8-12 weeks of age 2 g / hm ² ), and scotch tape was attached to the same position, and peeling was repeated 20 times until the water evaporation reached about 40-50 g / hm ² . Subsequently, 20ul of 0.3% of the galactosyl ceramide of formula (2a) was applied immediately after the injury, 6 hours, 12 hours, and 24 hours later, and the other side was treated with no application. After 48 hours, the skin was removed using Biopsy Punch (STIEFEL, 10 mm) and immunostaining was performed for histological examination. The results are shown in Figs. 2A to 2C. The results are shown in Fig. FIG. 2 (a) is a photograph showing a skin in which a lipid layer has disappeared in a skin layer, FIG. 2 (b) a control group, and FIG. 2 (c) photographs after treating 0.3% galactosylceramide. As shown in Fig. 2, the barrier function of the epidermal layer can be seen in a tissue sample treated with galactosylceramide, compared with a control group not treated with galactosyl ceramide.

[Experimental Example 2: Restoration Effect of Damaged Skin Barrier 2]

The amount of water evaporation on both sides of the mice was measured with a TEWL instrument (TEWAMETER, TM210, Germany) using 10 mice of 8-12 week old uninfected guinea pigs (Sumataka Bio Korea, Korea) Normal skin about 10 ± 2 g / hm ² ), and scotch tape was attached to the same position and peeling was repeated 20 times until the water evaporation reached about 40-50 g / hm ² . Then, 0.3% of the galactosyl ceramide of formula (2b) was applied 20, immediately after the injury, 6 hours, 12 hours and 24 hours after the injury, and the other was applied with no application to the other. Water evaporation was measured immediately after the injury, 6 hours, 12 hours, 24 hours, and 48 hours after the passage of time, respectively. The results are shown in Fig. As shown in FIG. 3, treatment of galactosyl ceramide shows that the skin barrier restoration effect is high.

[ Experimental Example  3: Effect on atopic disease]

Ten patients with atopic dermatitis without genetic predisposition to atopic dermatitis were treated with 4 weeks of treatment with 0.3% of formula (2a) and (2b) respectively. After that, the results were confirmed in each patient. As a result, the symptoms of atopic dermatitis were remarkably alleviated in 6 out of 10 persons of both galactosyl ceramide 3 and galactosyl ceramide 3B, Showed little change. The relief of symptoms here means that the feeling of well-being is calmed down and the skin flare sinks.

Therefore, galactosyl ceramide 0.3% has a therapeutic effect against atopic dermatitis. No hypersensitivity reactions or other side effects to the galactosyl ceramide of formula (2a) and (2b) were found in any of the 10 patients. Therefore, it can be seen that the galactosyl ceramide does not cause hypersensitivity to the human body or side effects.

[Experimental Example 4: Hair protection effect]

The hair obtained from the same person was divided into two groups, one group containing 0.2% of Formula 2a and the other group containing 0.2% of Formula 2b. Each hair was divided into two halves, one end was immersed in water and the other half was immersed in an aqueous solution (0.2% aqueous solution of formula (2a) or (2b) for 2 hours and then dried at room temperature. (H ₂ O ₂ , manufactured by DC Chemical Co., Ltd.) for 30 minutes and then dried at room temperature to observe the degree of damage of the surface of the hair, a Field Emission Scanning Electron Microscope (FE-SEM) (Ion Sputter, E-130, HITACHI, Ltd), which is a SEM-only coating equipment, and coated with silver coating at 700 times magnification The results are shown in Figure 4. The left photograph shows the hair of the control group not treated with the galactosyl ceramide and the right hair is the hair treated with the galactosyl ceramide. System was confirmed that the radial scanning electron microscope galactosyl ceramide was observed with (FE-SEM) showing the effect to protect the hair to prevent damage due to an external stimulus.

A composition containing the glycosyl ceramide derivative of the present invention was prepared according to a conventional method at the following composition ratio, but the present invention is not limited to the following formulation examples.

Formulation Example 1: Flexible lotion (skin)

ingredient Content (% by weight) The glycosyl ceramide of formula (2a) or (2b) 0.3 1,3-butylene glycol 5.2 Oleyl alcohol 1.5 ethanol 3.2 Polysorbate 20 3.2 Benzophenone-9 2.0 Carboxyl vinyl polymer 1. 0 glycerin 3.5 Spices a very small amount Distilled water Balance system 100

Formulation Example 2: Milk lotion

ingredient Content (% by weight) The glycosyl ceramide of formula (2a) or (2b) 0.6 glycerin 5.1 Propylene glycol 4.2 Tocopherol 3.0 Stearic acid 1.0 Squalane 3.1 1,3-butylene glycol 2.5 Polysorbate 60 1.6 Spices a very small amount Distilled water Balance system 100

Formulation Example 3: Nourishing cream

ingredient Content (% by weight) The glucosyl ceramide of formula (2a) or (2b) 1.0 glycerin 4.0 vaseline 3.5 Triethanolamine 2.1 Liquid paraffin 5.3 Squalane 3.0 Wax 2.6 Tocopherol acetate 5.4 Spices a very small amount Distilled water Balance system 100

Formulation Example 4: External ointment prescription

The glycosyl ceramide and the oil component were heated and dissolved, and then an emulsifier, preservative and the like were added and the temperature was adjusted to 70 ° C. This was homogeneously mixed with a homomixer, followed by defoaming, filtration and cooling.

function ingredient content(%) chief ingredient The glycosyl ceramide of formula (2a) or (2b) 1.0 Oil component Petrolatum Balance Cetostearyl alcohol 2.0 lanolin 3.0 Squalane 3.0 Emulsifier Ceteareth-20 3.0 antiseptic Propylparaben Proper amount Methylparaben Proper amount

Claims (16)

A glycosyl ceramide compound represented by the following formula (1).
[Chemical Formula 1]

In this formula,
n is an integer of 1 to 4,
m is an integer of 1 to 4,
R ₂ and R ₃ are hydrogen, R ₁ is a glycosyl group, the glycosyl group is a hexose,
R ₄ is an alkyl group or an alkenyl group having a carbon number of 17, and R ₅ is an alkyl group having a carbon number of 14. delete delete The method according to claim 1,
The hexose sugar is galactosyl glycosyl ceramide compound. The method according to claim 1,
Wherein the glycosyl group is bonded to the ceramide at the carbon position 6 of the saccharide saccharide. delete The method according to claim 1,
The glycosyl ceramide compound may be,
A glycosyl ceramide compound represented by the following formula (2a) or (2b).
(2a)

(2b)

8. A method for producing a glycosyl ceramide compound according to any one of claims 1 to 7,
A method for producing a glycosyl ceramide compound, which comprises reacting a ceramide and a diacetal galactose. 9. The method of claim 8,
Reacting a compound of formula (3a) or (3b) with diacetal galactose.
[Chemical Formula 3]

(3b)

7. A cosmetic composition comprising a compound according to any one of claims 1, 4, 5 and 7 as an active ingredient. 11. The cosmetic composition according to claim 10, wherein the composition contains 0.001 to 80% by weight of the compound of formula (1). [Claim 11] The cosmetic composition according to claim 10, wherein the cosmetic composition has the use of improving skin barrier function, improving skin elasticity, repairing damaged skin, moisturizing skin, improving wrinkles of skin, preventing skin aging, improving hair condition or alleviating atopic skin . A medicinal composition for preventing, ameliorating or treating a skin disease comprising the compound according to any one of claims 1, 4, 5 and 7 as an active ingredient. The pharmaceutical composition according to claim 13, wherein the composition contains 0.001 to 80% by weight of the compound of formula (1). delete The pharmaceutical composition according to claim 13, wherein the skin disease is atopic dermatosis or atopic dermatitis.

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