KR101175193B1 - Composition for skin disease comprising ceramide-hyaluronic composite - Google Patents

Abstract

The present invention relates to a therapeutic agent for skin diseases comprising the ceramide-containing hyaluronic acid complex as an active ingredient, and more particularly, to a composition for skin diseases such as excellent moisturizing effect and atopic dermatitis and psoriasis symptom relief by the ceramide-containing hyaluronic acid complex. will be.

The atopic dermatitis treatment or psoriasis symptom relief composition of the present invention contains the ceramide-containing hyaluronic acid complex of [Formula 1] or [Formula 2] as an active ingredient.

[Formula 1]

[Formula 2]

Here, A is 4-chloromethylbenzoyl chloride or 2-chloroacetyl chloride as a linker and ester bonds with ceramide.

Hyaluronic Acid, Ceramide, Moisturizing, Atopic Dermatitis, Cholesterol

Description

Composition for skin diseases containing ceramide-containing hyaluronic acid complex {COMPOSITION FOR SKIN DISEASE COMPRISING CERAMIDE-HYALURONIC COMPOSITE}

The present invention relates to a therapeutic agent for skin diseases comprising the ceramide-containing hyaluronic acid complex as an active ingredient, and more particularly, to a composition for skin diseases such as excellent moisturizing effect and atopic dermatitis and psoriasis symptom relief by the ceramide-containing hyaluronic acid complex. will be.

Human skin acts as a barrier to physical and chemical stimuli from the external environment. As the skin ages, the content of ceramide in the stratum corneum decreases as the skin ages, which reduces the adhesion of keratinocytes to the skin surface. You will not be protected. That is, as the content of ceramide 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 peeling of keratinocytes.

When the stratum corneum is damaged by skin aging or external stimulation, and the content of ceramide in the stratum corneum decreases, it has been reported that supplementing ceramide externally restores the lamellar structure of the skin and restores the skin to a normal state. . However, ceramides have limitations in formulation due to their stereochemical structure and hydrophobicity, so they can be used only in small amounts when manufacturing these products such as various solvents, cosmetics, and cleaning products. It does not have the disadvantage.

In addition, the above-mentioned atopic dermatitis (atopicdermatitis), although the cause is not clearly identified, symptoms such as severe itching, skin dryness, rash, rash, inflammation, infiltration, lichenitis, etc. are allergic diseases. It is also called by allergic people, especially accompanied by allergic rhinitis, asthma, and other allergic diseases, and is understood as one of genetic factors and immune diseases. The disease is characterized by an initial severe itching, which may be exacerbated by secondary infections and mental stability and emotional state of the patient. Moreover, it is frequent in people with dry skin, those with weak skin or lack of resistance, and is often caused by hypersensitivity reactions by various pollutants and bacteria such as staphylococci. In particular, various contaminants, bacteria, volatile organic compounds in the air, and ozone, which cause skin hypersensitivity reactions, synergistically exacerbate the symptoms of atopic dermatitis. Such atopic dermatitis is gradually increasing in recent years, but the treatment is not easy, and the cause is not identified, and most of them rely on symptomatic treatment. Recently, it is known that atopic dermatitis is caused by an immunological abnormality, and new therapeutic agents have been tried accordingly.

Drugs such as corticosteroids are used for the treatment of atopic dermatitis, but it is also well known that side effects are a problem and rebound (a dramatic worsening of the lesions after discontinuation of the drug) occurs when the drug is discontinued during treatment. . As a countermeasure against such side effects, nonsteroidal anti-inflammatory agents or antihistamines, which do not contain hormones such as corticosteroids, are used, and immunosuppressive agents are used in severe cases. However, most of these drugs are also temporary and have side effects such as osteoporosis, avascular necrosis, arteriosclerosis, glaucoma, and the possibility of carcinogenesis. Therefore, for the improvement and treatment of atopic dermatitis, there is an urgent need for the development of a new therapeutic agent having a good therapeutic effect, fewer side effects, and a continuous therapeutic effect.

It is mentioned in Korean Patent Publication No. 10-2008-0077432 as a specific mechanism of action of the antigen-specific IgE-class antibodies that cause allergic diseases. In fact, at 80 o to 90% of patients with atopic dermatitis, and the serum IgE is increased, when the serum IgE increase, it has been known as a potential allergic diseases (Cellular and Molecular Immunology, Abbas et al., 2 ^nd Edition , Saunders, Phildephia, Journal of Dermatological Science, 36, 1-9, 2004).

In this regard, the present invention finds that the composition comprising the ceramide-containing hyaluronic acid complex has an excellent moisturizing effect and is effective for the improvement and treatment of skin diseases including atopic dermatitis, and based on the pharmaceutical composition and the cosmetic composition I would like to propose.

The problem to be solved by the present invention is to provide a composition for skin diseases comprising a ceramide-containing hyaluronic acid complex for excellent moisturizing effect and treatment of atopic dermatitis or psoriasis symptoms by the ceramide-containing hyaluronic acid complex.

Another solution of the present invention is to use a ceramide-containing hyaluronic acid complex to overcome the limitations of ceramide, which could not be used on water (skin), to have a smooth feeling, and to contain ceramide for treating atopic dermatitis or psoriasis symptom relief with high absorption ability. It is to provide a composition for skin diseases comprising the hyaluronic acid complex.

Another object of the present invention to provide a therapeutic agent for atopic dermatitis or psoriasis containing a ceramide-containing hyaluronic acid complex as an active ingredient.

The composition for skin diseases containing the ceramide-containing hyaluronic acid complex of the present invention has the ceramide-containing hyaluronic acid complex of [Formula 1] or [Formula 2] as an active ingredient.

[Formula 1]

[Formula 2]

여기서, A는 링커로서 4-클로로메틸벤조일 클로라이드 또는 2-클로로아세틸 클로라이드이며, 세라미드와 에스터 결합한다.

Here, A is 4-chloromethylbenzoyl chloride or 2-chloroacetyl chloride as a linker and ester bonds with ceramide.

At this time, the ceramide-containing hyaluronic acid complex of [Chemical Formula 1] or [Chemical Formula 2] is preferably included in an amount of 0.1 to 50% by weight based on the total weight of the composition.

In addition, the present invention can be used as a therapeutic agent for atopic dermatitis or psoriasis as a therapeutic agent containing the ceramide-containing hyaluronic acid complex of [Formula 1] or [Formula 2] as an active ingredient.

The composition containing the ceramide-containing hyaluronic acid complex according to the present invention binds hyaluronic acid, a hydrophilic natural polymer, to ceramide, which is a representative lipid material, and shows an excellent moisturizing effect and an effect on improving and treating skin diseases including atopic dermatitis.

In addition, the present invention has a smooth feeling of use, and can be used as a therapeutic agent for atopic dermatitis or psoriasis having high absorption.

In addition, the composition according to the present invention can be applied to pharmaceutical compositions and cosmetic compositions such as gels, skins, creams and ointments.

The present invention increases the stability of various ceramides, especially in an aqueous medium, by combining ceramide, which is a representative lipid substance, with hyaluronic acid, a hydrophilic natural polymer, as an active ingredient of ceramide-containing hyaluronic acid of [Formula 1] or [Formula 2]. By improving the formulation limit of ceramide.

[Formula 1]

[Formula 2]

여기서, A는 링커로서 4-클로로메틸벤조일 클로라이드 또는 2-클로로아세틸 클로라이드이며, 세라미드와 에스터 결합한다.

Here, A is 4-chloromethylbenzoyl chloride or 2-chloroacetyl chloride as a linker and ester bonds with ceramide.

In the ceramide-containing hyaluronic acid complex of Formula 1, an activator is added to an aqueous solution of hyaluronic acid to generate a hyaluronic acid mixed solution in which a carboxylic acid moiety of hyaluronic acid is activated, and a basic reagent is mixed with the activated hyaluronic acid mixture. Step, and adding the activated hyaluronic acid produced in step a while dissolving ceramide in an amphoteric solvent, the carboxylic acid portion of the activated hyaluronic acid and the primary alcohol portion of the ceramide are reacted. It is produced in step b to produce a ceramide-hyaluronic acid complex.

The hyaluronic acid in step a is composed of hyaluronic acid itself, inorganic salts such as sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronic acid, and tetrabutylammonium hyaluronic acid. It includes everything.

The activator is added for the purpose of preparing the activated carbonyl group and the amount added is used in one equivalent of the single unit of hyaluronic acid. In this case, when the activator is used in an amount of 1 equivalent or more, it is preferable to use only 1 equivalent because the production cost increases. As such an activator, ethylenediamine hydrochloride (EDC), dicarboeximide (DCC) and the like are used.

Basic reagents are introduced to form hyaluronic acid anions. At this time, the basic reagent is effective using only 1 equivalent and triethylamine, dimethylamine, diethylamine, diisopropylamine, trimethylamine, enmethylmorpholine, pyrrolidine and the like can be used in addition to hydroxysuccinamide.

In step b, ceramide may be uniformly mixed with the activated hyaluronic acid by dissolving ceramide in an amphoteric solvent. The amphoteric solvent is tetrahydrofuran (THF), dimethylamide (DMF) and the like. Ceramides are represented by the following chemical formulas: DS Y30 Ceramide, PC 102 Ceramide, PC104 Ceramide, PC 107 Ceramide, PC 108 Ceramide, LC S20 Ceramide, Tocomide, PC 9S Ceramide, Questamide H (Questamide H or Pseudoceramide H).

DS Y30 Ceramide (N-Oleoyl-phytosphingosine)

PC-102 Ceramide (1,3-bis (N-2- (hydroxyethyl) lauroylamino) -2-hydroxy propane)

PC-104 ceramide

(1,3-bis (N-2- (hydroxyethyl) palmitoylamino) -2-hydroxy propane)

PC-107 Ceramide (1,3-bis (N-2- (hydroxyethyl) isostearoylamino) -2-hydroxy propane)

PC-108 Ceramide (1,3-bis (N-2- (hydroxyethyl) stearoylamino) -2-hydroxy propane)

Ceramide LC S-20 (1,3-bis (N-2- (hydroxyethyl) stearoylamino) -2-hydroxy propane)

Tocomid (Bis-Hydroxyethyl Tocopherylsuccinoylamido Hydroxypropane)

PC-9S (neopharm) ceramide (N- (1,3-Dihydroxyisopropyl) -3-oxo-2-tetradecyl / hexadecyl-octadec ana mide / eicosanamide)

Questamide H (bis-hydroxyethyl bis-cetyl malonamide), Pseudoceramide H)

In addition, the ceramide linker (A) -containing hyaluronic acid complex represented by [Formula 2] is prepared by adding tetraalkylammonium hydroxide to an aqueous hyaluronic acid solution to prepare a water-soluble hyaluronic acid tetraalkylammonium salt, and a linker to ceramide. Step (A) is mixed to prepare a linker introduced ceramide, and step C, wherein the hyaluronic acid tetraalkylammonium salt produced in step A and the ceramide linker (A) produced in step B are reacted with an organic solvent. .

Step A is prepared by adding hyaluronic acid (HA) with water to 0.6-1 equivalent of tetraalkylammonium hydroxide and then lyophilizing. In this case, tetraalkylammonium hydroxide is tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, tetrabutylammonium hydroxide, tetrapentylammonium hydroxide, in addition to tetrabutylammonium hydroxide. Organic salts such as tetrahexyl ammonium hydroxide, tetraheptyl ammonium hydroxide, tetraoctyl ammonium hydroxide, and the like, and preferably 0.8 equivalents of tetrabutylammonium hydroxide are used. The molecular weight of hyaluronic acid in the present invention is not particularly limited, but particularly preferably having a size of 4 to 10,000 kDa.

The linker (A) used in step B is ester-linked to the primary alcohol portion of the ceramide and is either 4-chloromethylbenzoyl chloride (hereinafter referred to as "linker A1") or 2-chloroacetyl chloride (hereinafter referred to as "linker A2" Is used). In addition, it is preferable that the ceramide is mixed after dissolving in a basic catalyst and the linker is mixed after dissolving in a solvent. As the basic catalyst, one equivalent of triethylamine, dimethylamine, diethylamine, diisopropylamine, trimethylamine, N-methylmorpholine and pyrrolidine may be used, and preferably one equivalent of triethylamine is used. It can be manufactured effectively. It is preferable to use tetrahydrofuran as a solvent.

The ceramide to which the linker (A) is introduced in step C generates a ceramide linker hyaluronic acid complex by reacting the carboxylic acid moiety of hyaluronic acid with the chloride moiety of the linker moiety. In this case, the ceramide in which the linker is introduced is added in an amount of 0.015 equivalents to 0.15 equivalents based on the hyaluronic acid tetrabutylammonium salt, and the organic compound of tetrahydrofuran / acetonitrile (THF / AN = v / v 1/4) is used as an amphoteric solvent. The reaction can be carried out together with the solvent, and preferably 0.05 equivalent can be prepared effectively.

The ceramide-containing hyaluronic acid complex of [Chemical Formula 2] generated through step C may remove impurities from the reaction solution to generate a pure ceramide linker (A) -containing hyaluronic acid complex.

On the other hand, the ceramide-containing hyaluronic acid complex of the present invention is prepared by being contained in a pharmaceutical composition and a cosmetic composition. The ceramide-containing hyaluronic acid complex contains 0.1 to 50% by weight, preferably 1 to 20% by weight, based on the total weight. If the content of ceramide-containing hyaluronic acid complex is less than 0.1% by weight, it is difficult to exert an effective effect when used in the product.When the content of ceramide-containing hyaluronic acid is more than 50% by weight, it is difficult to completely dissolve in water or deteriorate the feeling of use. Inappropriate.

The pharmaceutical composition may preferably be a pharmaceutical composition or cosmetic composition comprising one or more pharmaceutically acceptable carriers or excipients. For example, it may be prepared in the form of a cosmetic or cosmetic additive.

As the carrier or excipient, for example, solvents, oils, emulsifiers, preservatives can be preferably used, these materials can be used alone or in combination of two or more, and can be easily selected and used in the preparation of the composition. have.

As the solvent, water, ethanol, isopropanol, 1,3-butylene glycol, glycerol may be used.

The oil may include corn oil, sesame oil, cotton seed oil, peanut oil, mono-, di- and tri-glycerides. ), Mineral oil, squalene, jojoba oil, olive oil, evening primrose oil, borage oil, grape seed oil ) Can be used.

As the emulsifier, lecithin, organic acid monoglyceride, sorbitan ground acid ester, polyoxyethylene fatty acid ester, sorbitan stearate and the like can be used.

As the preservative, Methyl Paraben, Buthyl Paraben, Ethyl Paraben, Phenxyethanol, 1,2-Hexanediol, Chlorophenesin may be used.

The composition containing the ceramide-containing hyaluronic acid complex according to the present invention as an active ingredient may be applied to pharmaceutical compositions and cosmetic compositions such as gel type, skin type, cream type, ointment type, but is not limited thereto. The composition may be appropriately prepared by known methods by adding appropriate conventional softeners, emulsifiers, thickeners or other materials known in the art, depending on the type thereof.

The gel-type composition may be prepared by adding a softener such as trimethylolpropane, polyethylene glycol or glycerin, a solvent such as propylene glycol, ethanol, isotropic alcohol, refined liquor and the like.

The skin type composition may be selected from fatty alcohols such as stearyl alcohol, myristyl alcohol, behenyl alcohol, arachidyl alcohol, isostearyl alcohol, isocetyl alcohol, butylene glycol, glycerin, allantoin, methyl paraben, ideti- 2-sodium, xanthan gum, dimethicone, polyethylene glycol-60 hydrogenate castol oil, polysorbate 60, purified water and the like can be added.

The cream type composition may be a fatty alcohol such as stearyl alcohol, myristyl alcohol, behenyl alcohol, arachidyl alcohol, isostearyl alcohol, isocetyl alcohol, lecithin, phosphatidylcholine, phosphatidylethanolamine, sorbatizylserine, sorbatidyl Lipids such as inositol, derivatives thereof, emulsifiers such as glyceryl stearate, sorbitan palmitate, and sobitan stearate, natural fats or oils such as avocado oil, apricot oil, babassu oil, free acid oil, camellia oil, It can be prepared by adding a solvent such as propylene glycol and purified water.

The ointment type composition may be prepared by adding a softener, an emulsifier and waxes such as microcrystalline lead, paraffin, ceresin, beeswax, braze, petrolatum and the like.

The present invention may also be provided in a formulation comprising the compositions and one or more pharmaceutically acceptable carriers or excipients as active ingredients.

Thus, such formulations may include pharmaceutically acceptable carriers, diluents, excipients, or combinations thereof as needed. These formulations facilitate the administration of the active ingredient into the organism.

Such carriers are defined as compounds that facilitate the addition of compounds into cells or tissues. The carrier may be used without any particular limitation in the type normally used according to the formulation, preferably solid carriers such as starch, lactose, mannitol, carboxymethylcellulose, corn starch, inorganic salts, distilled water, saline solution, aqueous glucose solution, ethanol At least one selected from the group consisting of alcohol carriers such as alcohol, propylene glycol and polyethylene glycol, oily carriers such as various animal and vegetable oils, white petrolatum, paraffin and wax.

Such diluents are defined as compounds which not only stabilize the biologically active form of the subject compound, but also are diluted in water to dissolve the compound. Salts dissolved in buffer solutions are used as diluents in the art. The buffer solution used in general is phosphate buffered saline, because it mimics the salt state of the phosphoric acid solution. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely modify the biological activity of a compound.

Such excipients include, for example, fillers such as lactose, sucrose, mannitol, or sorbitol, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragakenth, methyl cellulose, hydroxypropylmethyl Cellulose based materials such as cellulose, sodium carboxymethyl cellulose and polyvinylpyrrolidone.

Hereinafter, in a preferred embodiment, the pharmaceutical preparation may be an external preparation, and such external preparation may be prepared based on a sterilized aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a freeze-dried preparation, etc. according to a conventional method. .

Hereinafter, the present invention will be described in more detail with reference to Examples, but the following Examples are provided to illustrate the present invention, and the scope of the present invention is not limited thereto. The composition prepared in the embodiment of the present invention may be applied to pharmaceutical compositions and cosmetic compositions such as gel type, skin type, cream type, ointment type, but is not limited thereto.

Example 1 Gel Type Composition of DS Y30 Ceramide-Containing Hyaluronic Acid Complex

Step a): 20 ml of water is added to 3 g (7.32 mmol) of HA (hyaluronic acid) (4.7 kDa) and stirred uniformly, 0.29 g (1.51 mmol) of ethylenediamine hydrochloride (EDC) as an activator and a basic reagent 0.174 g (1.51 mmol) of N-Hydroxysuccinimide was added and stirred at room temperature for 1 hour.

b) step: dissolve 0.426 g (0.732 mmol) of DS Y30 ceramide in 20 ml of tetrahydrofuran (THF) as an amphoteric solvent, add to the reaction solution, and add the activated hyaluronic acid produced in step a) to room temperature. It was stirred for 18 hours at to prepare a DS Y30 ceramide-containing hyaluronic acid complex. The stirred reaction solution was washed twice with 50 ml each of methylene chloride, and the water layer was dried under reduced pressure to remove all water. The reactants were dissolved in a small amount of purified water, and dialyzed in an excess of purified water for 18 hours with a dialysis membrane (3.5 kDa cut off) to remove impurities. After dialysis, the solution of lyophilized for 1 day to obtain 1.32 g (yield: 38.6%) of the hyaluronic acid (Hyaramide) complex containing the general formula (I) DS Y30 ceramide.

c) step: 10 wt% of the prepared DS Y30 ceramide-containing hyaluronic acid complex is added to 5 g of distilled water and heated to 40 ° C., followed by stirring for 5 minutes to prepare an aqueous phase solution. A water phase part solution was added to 40 g of a gel type composition having the composition ratio of [Table 1] heated to the same temperature to prepare a composition.

Table 1 Gel-type composition comprising ceramide-containing hyaluronic acid complex

ingredient weight(%) Ceramide-containing hyaluronic acid complex Example Weight (%) Carboxyvinyl polymer 1.0 Triethanolamine 1.0 Butylene Glycol 5.0 glycerin 10.0 Hydrogenated Castor Oil 1.0 Preservative, incense Suitable amount Purified water Balance Sum 100

<Examples 2-15>

A gel-type composition was prepared in the same manner as in Example 1, except that the ceramide of [Table 2] was used in the ceramide-containing hyaluronic acid complex of Example 1.

[Table 2] Gel-type composition comprising ceramide-containing hyaluronic acid complex

Ceramide type of ceramide-containing hyaluronic acid complex Participation amount (% by weight) Example 1 DS Y30 Ceramide 10 Example 2 PC 102 Ceramides 10 Example 3 PC 104 Ceramides 10 Example 4 PC 107 Ceramides 10 Example 5 PC 108 Ceramides 10 Example 6 LC S20 Ceramide 10 Example 7 Tocomide 10 Example 8 PC 9S Ceramides 10 Example 9 Questamid H 10 Example 10 DS Y30 Ceramide One Example 11 DS Y30 Ceramide 5 Example 12 DS Y30 Ceramide 20

Example 13 Skin Type Composition of DS Y30 Ceramide-Containing Hyaluronic Acid Complex

A skin type composition was prepared in the same manner as in Example 1, except for adding the aqueous phase solution to 40 g of the skin type composition having the composition ratio of Table 3 in Step c) of Example 1.

Table 3 Skin type composition comprising ceramide-containing hyaluronic acid complex

ingredient weight(%) Ceramide-containing hyaluronic acid complex Example Weight (%) Concentrated glycerin 10 Propylene glycol 10 Poly cloth ethylene hardened castor oil (E040) 1.0 Sodium hyaluronate aqueous solution (1%) 5.0 ethanol 5.0 Preservative, incense Suitable amount Purified water Balance Sum 100

<Examples 14-24>

A skin type composition was prepared in the same manner as in Example 13, except that the ceramide of [Table 4] was used in the ceramide-containing hyaluronic acid complex of Example 1.

[Table 4]

Ceramide type of ceramide-containing hyaluronic acid complex Participation amount (% by weight) Example 13 DS Y30 Ceramide 10 Example 14 PC 102 Ceramides 10 Example 15 PC 104 Ceramides 10 Example 16 PC 107 Ceramides 10 Example 17 PC 108 Ceramides 10 Example 18 LC S20 Ceramide 10 Example 19 Tocomide 10 Example 20 PC 9S Ceramides 10 Example 21 Questamid H 10 Example 22 DS Y30 Ceramide One Example 23 DS Y30 Ceramide 5 Example 24 DS Y30 Ceramide 20

Example 25 Cream-Type Composition of DS Y30 Ceramide-Containing Hyaluronic Acid Complex

A cream type composition was prepared in the same manner as in Example 1, except that the aqueous phase solution was added to 40 g of the cream type composition having the composition ratio of Table 5 in Step c) of Example 1.

Table 5 Cream type composition comprising ceramide-containing hyaluronic acid complex

ingredient weight(%) Ceramide-containing hyaluronic acid complex Example Weight (%) Stearyl alcohol 6.0 Stearic acid 2.0 Concentrated glycerin 1.0 Squalane 9.0 1,3-butylene glycol 6.0 Polysorbate 60 1.5 Polyethylene glycol 1000 4.0 Cured Lanolin 4.0 Octyl dodecanol 10.0 Sorbitan stearate 0.8 Triethanolamine 0.5 Preservative, incense Suitable amount Purified water Balance Sum 100

<Examples 26-36>

A cream type composition was prepared in the same manner as in Example 25, except that the ceramide of [Table 6] was used in the ceramide-containing hyaluronic acid complex of Example 1.

TABLE 6

Ceramide type of ceramide-containing hyaluronic acid complex Participation amount (% by weight) Example 25 DS Y30 Ceramide 10 Example 26 PC 102 Ceramides 10 Example 27 PC 104 Ceramides 10 Example 28 PC 107 Ceramides 10 Example 29 PC 108 Ceramides 10 Example 30 LC S20 Ceramide 10 Example 31 Tocomide 10 Example 32 PC 9S Ceramides 10 Example 33 Questamid H 10 Example 34 DS Y30 Ceramide One Example 35 DS Y30 Ceramide 5 Example 36 DS Y30 Ceramide 20

Example 37 Ointment Type Composition of DS Y30 Ceramide-Containing Hyaluronic Acid Complex

An ointment type composition was prepared in the same manner as in Example 1, except that 45 g of the ointment type composition having the composition ratio of [Table 7] was added in step c) of Example 1.

[Table 7] Ointment type composition comprising a ceramide-containing hyaluronic acid complex

ingredient weight(%) Ceramide-containing hyaluronic acid complex Example Weight (%) Diethyl sebacate 8.0 Prepayment 5.0 Polyoxyethylene Oleyl-Ether Phosphate (0 4) 6.0 Sodium benzoate Suitable amount Vaseline Balance Sum 100

<Examples 38-48>

An ointment type composition was prepared in the same manner as in Example 37, except that the ceramide of [Table 8] was used in the ceramide-containing hyaluronic acid complex of Example 1.

[Table 8]

Ceramide type of ceramide-containing hyaluronic acid complex Participation amount (% by weight) Example 37 DS Y30 Ceramide 10 Example 38 PC 102 Ceramides 10 Example 39 PC 104 Ceramides 10 Example 40 PC 107 Ceramides 10 Example 41 PC 108 Ceramides 10 Example 42 LC S20 Ceramide 10 Example 43 Tocomide 10 Example 44 PC 9S Ceramides 10 Example 45 Questamid H 10 Example 46 DS Y30 Ceramide One Example 47 DS Y30 Ceramide 5 Example 48 DS Y30 Ceramide 20

Example 49 Gel Type Composition of DS Y30 Ceramide Linker (A1) -Containing Hyaluronic Acid Complex

Step A): 60 g of water (5.12 mmol) in HA (hyaluronic acid) (4.7 kDa) and tetra-n-butylammonium hydroxide, 40 WT.% In activator 6.34 g (9.77 mmol) of H ₂ O) solution were added, uniformly stirred for 30 minutes, and lyophilized to prepare 7.96 g (yield 100%) of activated hyaluronic acid tetrabutylammonium salt.

B) step: To 5 g (8.59 mmol) of DS Y30 ceramide, 25 ml of tetrahydrofuran (THF) and 0.96 g (9.45 mmol) of triethylamine were dissolved. 1.62 g (8.59 mmol) of A1 (4-chloromethylbenzoyl chloride) was dissolved in 10 ml of tetrahydrofuran and added, followed by stirring at 55˜60 ° C. for 6 hours. After completion of the reaction, the resulting triethylamine hydrochloride was removed by filtration, and the filtered solution was concentrated to remove the organic solvent, and then recrystallized in 120 ml of ethanol / methanol (v / v = 5/1) to yield 3.45 g (yield 53.6). %) Was obtained.

C) step: 5.0 g (8.10 mmol) of the hyaluronic acid tetrabutylammonium salt obtained in step A) were dissolved in an organic solvent of tetrahydrofuran / acetonitrile (v / v = 1/4), and then obtained in step B). 0.30 g (0.41 mmol) of DS Y30 ceramide containing linker (A1) was added thereto, followed by stirring at 35 to 40 ° C for 5 hours. After completion of the reaction, the reaction solution was passed through celite to remove impurities, concentrated under reduced pressure to remove an organic solvent, and the concentrated reactant was dissolved in 100 ml of water and freeze-dried to produce a ceramide linker (A1). ) 7.7 g (yield 89.0%) of hyaluronic acid complexes were obtained.

D) step: 5 g of the prepared DS Y30 ceramide linker (A1) -containing hyaluronic acid complex was added to 5 g of distilled water and heated to 40 ° C., followed by stirring for 5 minutes to prepare an aqueous phase solution. The gel-type composition was prepared by sufficiently adding an aqueous phase solution to 40 g of the gel-type composition having the composition ratio of Table 1 of Example 1 heated to the same temperature.

<Examples 50-60>

A gel-type composition was prepared in the same manner as in Example 49, except that the ceramide of [Table 9] was used in the ceramide-containing hyaluronic acid complex of Example 49.

TABLE 9

Ceramide type of ceramide linker (A1) containing hyaluronic acid complex Participation amount (% by weight) Example 49 DS Y30 Ceramide 10 Example 50 PC 102 Ceramides 10 Example 51 PC 104 Ceramides 10 Example 52 PC 107 Ceramides 10 Example 53 PC 108 Ceramides 10 Example 54 LC S20 Ceramide 10 Example 55 Tocomide 10 Example 56 PC 9S Ceramides 10 Example 57 Questamid H 10 Example 58 DS Y30 Ceramide One Example 59 DS Y30 Ceramide 5 Example 60 DS Y30 Ceramide 20

Example 61 Skin Type Composition of DS Y30 Ceramide Linker (A1) -Containing Hyaluronic Acid Complex

A skin type composition was prepared in the same manner as in Example 49, except that the aqueous phase solution was added to 40 g of the skin type composition having the composition ratio of [Table 3] of Example 13 in Step D) of Example 49.

<Examples 62-72>

A skin type composition was prepared in the same manner as in Example 61, except that the ceramide of [Table 10] was used in the ceramide-containing hyaluronic acid complex of Example 49.

TABLE 10

Ceramide type of ceramide linker (A1) containing hyaluronic acid complex Participation amount (% by weight) Example 61 DS Y30 Ceramide 10 Example 62 PC 102 Ceramides 10 Example 63 PC 104 Ceramides 10 Example 64 PC 107 Ceramides 10 Example 65 PC 108 Ceramides 10 Example 66 LC S20 Ceramide 10 Example 67 Tocomide 10 Example 68 PC 9S Ceramides 10 Example 69 Questamid H 10 Example 70 DS Y30 Ceramide One Example 71 DS Y30 Ceramide 5 Example 72 DS Y30 Ceramide 20

Example 73 Cream-Type Composition of Hyaluronic Acid Complex Containing DS Y30 Ceramide Linker (A1)

A cream type composition was prepared in the same manner as in Example 49, except that the aqueous phase solution was added to 40 g of the cream type composition having the composition ratio of [Table 5] of Example 25 in Step D) of Example 49.

<Examples 74 to 84>

A cream type composition was prepared in the same manner as in Example 73, except that the ceramide of [Table 11] was used in the ceramide-containing hyaluronic acid complex of Example 49.

TABLE 11

Ceramide type of ceramide linker (A1) containing hyaluronic acid complex Participation amount (% by weight) Example 73 DS Y30 Ceramide 10 Example 74 PC 102 Ceramides 10 Example 75 PC 104 Ceramides 10 Example 76 PC 107 Ceramides 10 Example 77 PC 108 Ceramides 10 Example 78 LC S20 Ceramide 10 Example 79 Tocomide 10 Example 80 PC 9S Ceramides 10 Example 81 Questamid H 10 Example 82 DS Y30 Ceramide One Example 83 DS Y30 Ceramide 5 Example 84 DS Y30 Ceramide 20

Example 85 Ointment Type Composition of Hyaluronic Acid Complex Containing DS Y30 Ceramide Linker (A1)

An ointment type composition was prepared in the same manner as in Example 49, except that 45 g of an ointment type composition having the composition ratio of Table 7 of Example 37 was added in step D) of Example 49.

<Examples 86-96>

An ointment type composition was prepared in the same manner as in Example 85, except that the ceramide of [Table 12] was used in the ceramide-containing hyaluronic acid complex of Example 49.

[Table 12]

Ceramide type of ceramide linker (A1) containing hyaluronic acid complex Participation amount (% by weight) Example 85 DS Y30 Ceramide 10 Example 86 PC 102 Ceramides 10 Example 87 PC 104 Ceramides 10 Example 88 PC 107 Ceramides 10 Example 89 PC 108 Ceramides 10 Example 90 LC S20 Ceramide 10 Example 91 Tocomide 10 Example 92 PC 9S Ceramides 10 Example 93 Questamid H 10 Example 94 DS Y30 Ceramide One Example 95 DS Y30 Ceramide 5 Example 96 DS Y30 Ceramide 20

<Example 97> Gel type composition of DS Y30 ceramide linker (A2) containing hyaluronic acid complex

Step A): 60 g of water (5.12 mmol) in HA (hyaluronic acid) (4.7 kDa) and tetra-n-butylammonium hydroxide, 40 WT.% In activator 6.34 g (9.77 mmol) of H ₂ O) solution were added, uniformly stirred for 30 minutes, and lyophilized to prepare 7.96 g (yield 100%) of activated hyaluronic acid tetrabutylammonium salt.

B) step: To 5 g (8.59 mmol) of DS Y30 ceramide, 25 ml of tetrahydrofuran (THF) and 0.96 g (9.45 mmol) of triethylamine were dissolved. 1.62 g (8.59 mmol) of A2 (2-chloroacetyl chloride) was dissolved in 10 ml of tetrahydrofuran and added thereto, followed by stirring at 55˜60 ° C. for 6 hours. After completion of the reaction, the resulting triethylamine hydrochloride was removed by filtration, and the filtered solution was concentrated to remove the organic solvent, and then recrystallized in 120 ml of ethanol / methanol (v / v = 5/1) to yield 3.45 g (yield 53.6). %) Was obtained.

C) step: 5.0 g (8.10 mmol) of the hyaluronic acid tetrabutylammonium salt obtained in step A) were dissolved in tetrahydrofuran / acetonitrile (v / v = 1/4), and then the linker (A2) obtained in step B) ) 0.30 g (0.41 mmol) of DS Y30 ceramide was added thereto, followed by stirring at 35 to 40 ° C for 5 hours. After completion of the reaction, the reaction solution was passed through celite to remove impurities, concentrated under reduced pressure to remove an organic solvent, and the concentrated reactant was dissolved in 100 ml of water and freeze-dried to produce a ceramide linker (A2). ), 4.89 g (yield 95.1%) of hyaluronic acid complexes were obtained.

D) step: 5 g of the prepared DS Y30 ceramide-containing hyaluronic acid complex was added to 5 g of distilled water and heated to 40 ° C., followed by stirring for 5 minutes to prepare a water phase part solution. The gel-type composition was prepared by sufficiently adding an aqueous phase solution to 40 g of the gel-type composition having the composition ratio of Table 1 of Example 1 heated to the same temperature.

<Examples 98-108>

A gel type composition was prepared in the same manner as in Example 97, except that the ceramide of [Table 13] was used in the ceramide-containing hyaluronic acid complex of Example 97.

[Table 13]

Ceramide type of ceramide linker (A2) containing hyaluronic acid complex Participation amount (% by weight) Example 97 DS Y30 Ceramide 10 Example 98 PC 102 Ceramides 10 Example 99 PC 104 Ceramides 10 Example 100 PC 107 Ceramides 10 Example 101 PC 108 Ceramides 10 Example 102 LC S20 Ceramide 10 Example 103 Tocomide 10 Example 104 PC 9S Ceramides 10 Example 105 Questamid H 10 Example 106 DS Y30 Ceramide One Example 107 DS Y30 Ceramide 5 Example 108 DS Y30 Ceramide 20

Example 109 Skin Type Composition of Hyaluronic Acid Complex Containing DS Y30 Ceramide Linker (A2)

A skin type composition was prepared in the same manner as in Example 97, except that, in step D) of Example 97, the aqueous phase solution was added to 40 g of the skin type composition having the composition ratio of [Table 3] of Example 13.

<Examples 110 to 120>

A skin type composition was prepared in the same manner as in Example 109, except that the ceramide of [Table 14] was used in the ceramide-containing hyaluronic acid complex of Example 97.

[Table 14]

Ceramide type of ceramide linker (A2) containing hyaluronic acid complex Participation amount (% by weight) Example 109 DS Y30 Ceramide 10 Example 110 PC 102 Ceramides 10 Example 111 PC 104 Ceramides 10 Example 112 PC 107 Ceramides 10 Example 113 PC 108 Ceramides 10 Example 114 LC S20 Ceramide 10 Example 115 Tocomide 10 Example 116 PC 9S Ceramides 10 Example 117 Questamid H 10 Example 118 DS Y30 Ceramide One Example 119 DS Y30 Ceramide 5 Example 120 DS Y30 Ceramide 20

Example 121 Cream-Type Composition of Hyaluronic Acid Complex Containing DS Y30 Ceramide Linker (A2)

A cream type composition was prepared in the same manner as in Example 97, except that the aqueous phase solution was added to 40 g of the cream type composition having the composition ratio of [Table 5] of Example 25 in Step D) of Example 97.

<Examples 122-132>

A cream type composition was prepared in the same manner as in Example 121, except that the ceramide of [Table 15] was used in the ceramide-containing hyaluronic acid complex of Example 97.

TABLE 15

Ceramide type of ceramide linker (A2) containing hyaluronic acid complex Participation amount (% by weight) Example 121 DS Y30 Ceramide 10 Example 122 PC 102 Ceramides 10 Example 123 PC 104 Ceramides 10 Example 124 PC 107 Ceramides 10 Example 125 PC 108 Ceramides 10 Example 126 LC S20 Ceramide 10 Example 127 Tocomide 10 Example 128 PC 9S Ceramides 10 Example 129 Questamid H 10 Example 130 DS Y30 Ceramide One Example 131 DS Y30 Ceramide 5 Example 132 DS Y30 Ceramide 20

Example 133 Ointment Type Composition of DS Y30 Ceramide Linker (A2) -Containing Hyaluronic Acid Complex

An ointment type composition was prepared in the same manner as in Example 97, except that 45 g of an ointment type composition having a composition ratio of Table 7 of Example 37 was added in step D) of Example 97.

<Examples 134-144>

An ointment type composition was prepared in the same manner as in Example 133, except that the ceramide of [Table 16] was used in the ceramide-containing hyaluronic acid complex of Example 97.

TABLE 16

Ceramide type of ceramide linker (A2) containing hyaluronic acid complex Participation amount (% by weight) Example 133 DS Y30 Ceramide 10 Example 134 PC 102 Ceramides 10 Example 135 PC 104 Ceramides 10 Example 136 PC 107 Ceramides 10 Example 137 PC 108 Ceramides 10 Example 138 LC S20 Ceramide 10 Example 139 Tocomide 10 Example 140 PC 9S Ceramides 10 Example 141 Questamid H 10 Example 142 DS Y30 Ceramide One Example 143 DS Y30 Ceramide 5 Example 144 DS Y30 Ceramide 20

<Experiment 1> Moisturizing effect test / skin moisture content increase effect

The skin moisturizing effect of the ceramide-containing hyaluronic acid complex and hyaluronic acid of the present invention was examined. Example 1, Example 13, Example 14, Example 15, Example 16, Example 17, Example 18, Example 19, Example 20, Example 21, Example 22, Example 23 Cosmetic composition using only the cosmetic composition of Example 24, Example 25, Example 37, Example 61, Example 63, Example 65, Example 109, Example 111, and Example 113 and Comparative Example (hyaluronic acid) 40 people in their 20s and 40s without skin diseases were applied to the face twice a day for 1 month. Repeat the facial fold three times using the Koniometer CM825 (Courage + Khazaka Electronic GmbH., Cologne, Germany), a device that measures the amount of moisture in the skin at constant temperature and humidity conditions (24 ° C, 40% humidity) before starting application. It measured and calculated | required the average value. After 4 weeks from 0 weeks, the skin moisture content was measured, and the increase rate was evaluated by a paired-t test and is shown in the following [Table 17].

[Table 17] Moisturizing effect test / skin moisture content increase effect

Capacitance value (AU.) Week 0 2 weeks 4 weeks Comparative example (haaluronic acid) 40 48 53 Example 1 41 48 55 Example 13 40 54 73 Example 14 40 44 48 Example 15 39 55 69 Example 16 41 50 56 Example 17 41 48 64 Example 18 40 51 59 Example 19 43 46 54 Example 20 45 48 55 Example 21 41 46 53 Example 22 43 52 60 Example 23 42 53 63 Example 24 38 46 51 Example 25 37 50 62 Example 37 40 54 63 Example 61 39 56 75 Example 63 36 58 69 Example 65 44 60 71 Example 109 41 59 77 Example 111 40 54 68 Example 113 Synthesis of 38 51 66

As can be seen in [Table 17], as time passed, the comparative example (hyaluronic acid) and all the examples confirmed that the skin moisturizing effect is improved. In Example 13, Example 61 and Example 109 it showed an excellent skin moisturizing effect.

From the above results, it was confirmed that the ceramide-containing hyaluronic acid complex has an effect of improving skin moisturizing power, and excellent effect in Examples 13, 61, and 109.

Experimental Example 2: Ear Edema Test in Mice

In order to confirm the improvement and treatment effect of skin diseases including atopic dermatitis, a test was conducted with an ear edema model, which is one of the atopic animal models. The ear edema model induces atopy by sensitizing Hapten (a small-molecular-weight chemical that binds to proteins and becomes an allergen) to the mouse's ear, causing the ear to swell over time and increase the thickness of the ear. Animal model to measure and confirm the therapeutic effect of atopic dermatitis (Journal of Dermatological Scienece, 36, 1-9, 2004; Journal of Dermatological Scienece, 37, 159-167, 2005)

In this experiment, DNCB (2,4-dinitro-1-chloro-benzene, Sigma) was used as a Balb / C mouse (male, 5 weeks old) and hapten, and 5 animals were tested in each group. 30 μl of a solution of DNCB dissolved in acetone at 1% concentration was sensitized to the right ear of the mouse, and a week later, 30 μl of 1% concentration solution was applied daily to induce atopic dermatitis. At the same time, the solutions of Comparative Example (No Treatment), Example 1, Example 13, Example 25, Example 37, Example 61, and Example 109 were applied to the right ear 30 μl each twice daily, before DNCB sensitization. MRp of the ear was presented with digital micrometer on day 1 and day 3 of atopic induction. Increased ear thickness after atopic induction is shown in Table 18 below.

Table 18 Increased ear thickness (mm)

1 day 2 days 3 days Comparative example (no treatment) 201.1 257.3 302.5 Example 1 135.9 178.3 212.8 Example 13 126.4 128.7 130.1 Example 25 130.4 134.1 138.2 Example 37 129.8 146.2 158.9 Example 61 127.1 127.7 128.1 Example 109 125.9 126.8 130.3

As can be seen in [Table 18], as the atopic induction time elapsed, the comparative example (no treatment) significantly increased the thickness of the ear, and the results of the third day, Examples 1, 13, and implementation Example 25, Example 37, Example 61 and Example 109 were all found to have the effect of suppressing ear edema in atopic dermatitis-induced mice. Of these, Examples 13, 61 and 109 showed very good atopic treatment effects.

From the above results, it was confirmed that the ceramide-containing hyaluronic acid complex has an effect of treating atopic dermatitis, and excellent effect in Examples 13, 61 and 109.

Claims (13)

A composition for skin diseases comprising a ceramide-containing hyaluronic acid complex having the ceramide-containing hyaluronic acid complex of [Formula 1] or [Formula 2] as an active ingredient. [Formula 1]

[Formula 2]

Here, A is 4-chloromethylbenzoyl chloride or 2-chloroacetyl chloride as a linker and ester bonds with ceramide. The method of claim 1, wherein the ceramide-hyaluronic acid complex of [Formula 1], by adding an activator to the aqueous solution of hyaluronic acid to generate a hyaluronic acid mixed solution in which the carboxylic acid moiety of hyaluronic acid is activated, to the activated hyaluronic acid mixture Step a of mixing the basic reagent and the activated hyaluronic acid produced in step a while dissolving ceramide in an amphoteric solvent are added together with the carboxylic acid moiety of the activated hyaluronic acid and the primary alcohol of the ceramide ( A composition for skin diseases comprising a ceramide-containing hyaluronic acid complex prepared in step b to produce a ceramide-hyaluronic acid complex reacted with a primary alcohol) portion. The method of claim 1, wherein the ceramide linker (A) -containing hyaluronic acid complex of [Formula 2] is a step of preparing a water-soluble hyaluronic acid tetraalkylammonium salt by adding tetraalkylammonium hydroxide to an aqueous hyaluronic acid solution, and ceramide In step B of preparing a linker introduced ceramide by mixing a linker (A) and the hyaluronic acid tetraalkylammonium salt produced in step A and the ceramide linker (A) produced in step B with an organic solvent. Skin disease composition comprising a ceramide-containing hyaluronic acid complex prepared. The composition of claim 1, wherein the ceramide-containing hyaluronic acid complex of [Chemical Formula 1] or [Chemical Formula 2] comprises a ceramide-containing hyaluronic acid complex that is mixed at a total weight of 0.1 to 50% by weight. The composition according to claim 4, wherein the ceramide-containing hyaluronic acid complex of [Chemical Formula 1] or [Chemical Formula 2] comprises a ceramide-containing hyaluronic acid complex which is mixed at 1 to 20% by weight based on the total weight. delete The composition of claim 1, wherein the composition further comprises a ceramide-containing hyaluronic acid complex further comprising at least one pharmaceutically acceptable carrier or excipient selected from a solvent, an oil, an emulsifier, a preservative, and a mixture thereof. The skin disease composition of claim 7, wherein the solvent comprises any one selected from water, ethanol, isopropanol, 1,3-butylene glycol, and glycerol. The oil of claim 7, wherein the oil is corn oil, sesame oil, cotton seed oil, peanut oil, mono-, di- and tri- Glyceride, mineral oil, squalene, jojoba oil, olive oil, evening primrose oil, borage oil, grape seed oil Skin composition comprising a ceramide-containing hyaluronic acid complex which is any one selected from (grape seed oil). The method according to claim 7, wherein the emulsifier for skin diseases comprising a ceramide-containing hyaluronic acid complex which is any one selected from lecithin, organic acid monoglycerides, sorbitan ground acid esters, polyoxyethylene fatty acid esters, sorbitan stearate Composition. delete An atopic dermatitis or psoriasis treatment agent comprising the ceramide-containing hyaluronic acid complex of [Formula 1] or [Formula 2] as an active ingredient. [Formula 1]

[Formula 2]

Here, A is 4-chloromethylbenzoyl chloride or 2-chloroacetyl chloride as a linker and ester bonds with ceramide. The agent for treating atopic dermatitis or psoriasis according to claim 12, wherein the compound of [Formula 1] or [Formula 2] is 0.1 to 50% by weight based on the total weight of the composition.