KR100528033B1 - A pharmaceutical composition for the treatment of atopic dermatitis containing 4-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)-2-oxiranyl]-1-oxaspiro [2,5]octan-6-one - Google Patents

Abstract

The present invention provides a pharmaceutically effective amount of 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro It relates to a pharmaceutical composition for preventing or treating atopic dermatitis, containing [2,5] octane-6-one, which is believed to be intricately associated with genetic, environmental, and immunological factors.

Description

4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane-6- Pharmaceutical composition for treating atopic dermatitis containing ions [A PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF ATOPIC DERMATITIS CONTAINING 4-HYDROXY-5-METHOXY-4- [2-METHYL-3- (3-METHYL-2-BUTENYL) -2 -OXIRANYL] -1-OXASPIRO [2,5] OCTAN-6-ONE}

The present invention provides a pharmaceutically effective amount of 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro It relates to a pharmaceutical composition for preventing or treating atopic dermatitis, containing [2,5] octane-6-one, which is believed to be intricately associated with genetic, environmental, and immunological factors.

Atopic dermatitis is a common skin disease with a high incidence in infancy and childhood. The prevalence of atopic dermatitis has been reported from 3% to 15%, and extensive epidemiological studies have been conducted since the Second World War, and many studies have been conducted in Korea (see Hanifin JM. Et al., Ciagnostic features of atopic). dermatitis, Acta Derm Venereol, 1980, Suppl 92, 44-47; Diepgen TL et al., Recent epidemiological and genetic studies in atopic dermatitis, Acta Derm Venereol, 1992, Suppl 176, 13-18; Diepgen TL. et al., Evaluation and relevance of atopic base and minor features in patients with atopic dermatitis and in the general population, Acta Derm Venereol, 1989, Suppl 144, 50-54).

Atopic dermatitis is a chronic recurrent dermatitis that appears to be a genetic predisposition with severe pruritus, characteristic shape and distribution of skin lesions, and a personal or family atopic history. In recent years, atopic dermatitis has been increasing due to the effects of food additives and environmental pollution, and the exact etiology is unknown, but it is estimated that the disease is caused by a complex relationship between genetic, environmental and immunological factors (see Leung DYM). Et al., In: Fitzpatrick TB, et al eds, Dermatology in general medicine, 4th ed, New York: McGraw-Hill, 1993, 1543-1564; Morren MA et al., Atopic dermtitis: triggering factors, J Am Acad Dermatol, 1994, 31, 467-473).

In atopic dermatitis, a decrease in peripheral blood CD8 ⁺ T lymphocytes is observed, resulting in an increase in the ratio of CD4: CD8. Although this phenomenon does not induce a decrease in systemic cell-mediated immunity, it causes a decrease in skin immunity, which causes frequent viral or bacterial infections in patients with atopic dermatitis, and a decrease in response to contact allergens. In addition, the secretion of INF-γ and TNF-β in CD4 ⁺ T lymphocytes decreases the number of Th1 involved in normal cell-mediated immunity and increases the production of IgE, which induces allergic reactions by secreting IL-4. The number of Th2 that is directly involved in the cell is increased (see Bos JD et al., Immune dysregulation in atopic eczema, Arch Dermatol, 1992, 128, 1509; Del Prete G et al., Biology of disease, Human Th1 and Th2 cells: Functional properties). , mechanisms of regulation, and role in disease, Lab Invest 1994, 70, 299).

On the other hand, 80% of patients with atopic dermatitis have higher serum IgE than normal people, and the more severe the symptoms, the higher the level of IgE. Inhibition of increased IgE itself is directly involved in skin lesions. It is still unclear if this is the case (see Jones HE et al., Atopic disease and serum immunoglobulin-E, Br J Dermatol, 1975, 92, 17-25).

 In addition, damage to the epidermal barrier is observed in atopic patients. It is estimated that the lack of ceramide, a lipid component between keratinocytes in the epidermal stratum corneum, causes dryness by increasing transdermal moisture loss in atopic dermatitis.

Therefore, the use of a moisturizer that can prevent transdermal moisture loss in atopic dermatitis patients, it is essential, and in patients with mild atopic dermatitis it is possible to improve symptoms only by using a moisturizer.

Atopy-related products currently on the market for the purpose of preventing and / or treating atopy are based on steroids or plant extracts. However, the steroid system is being avoided by consumers due to side effects and resistance, and most atopy-related products use plant extract as a raw material, but the drug efficacy does not satisfy atopic patients.

Thus, despite the large number of publications and prototypes relating to the prevention, improvement and treatment of atopic dermatitis, there is still a need for the development of new substances and formulations that are highly effective and non-toxic against atopic dermatitis.

Accordingly, the present inventors have studied compounds that are not toxic and effective for the prevention or treatment of atopic dermatitis, resulting in compound 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2- Butenyl) -2-oxanyl] -1-oxaspiro [2,5] octane-6-one (hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxiranyl] -1-oxaspiro [2,5] octan-6-one) was found to show a high improvement effect on atopic dermatitis with little toxicity, thus completing the present invention.

Accordingly, an object of the present invention is a pharmaceutically effective amount of 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl]- It is to provide a pharmaceutical composition for treating atopic dermatitis containing 1-oxaspiro [2,5] octane-6-one.

In order to achieve the above object, the pharmaceutical composition for treating atopic dermatitis of the present invention is 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) as an active ingredient. ) -2-oxanyl] -1-oxaspiro [2,5] octan-6-one.

Hereinafter, the present invention will be described in more detail.

Term Definition

As used herein, the term "pharmaceutically effective amount" means an amount of a pharmaceutical composition that is applied to the skin condition to provide a prophylactic or therapeutic effect.

The term "pharmaceutical composition" as used herein refers to a pharmaceutically effective amount of 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2- Pharmaceutical preparations, detergents and cosmetics containing oxiranyl]-1-oxaspiro [2,5] octane-6-one as an active ingredient to prevent or treat skin conditions caused by atopic dermatitis Includes all cosmetics.

As used herein, the term "skin condition" refers to a condition in which the site of infection of the skin is changed by atopic dermatitis, which includes both a condition considered to be a skin disease and a condition not regarded as a skin disease.

As used herein, the term "treatment" includes the cure of atopic dermatitis symptoms as well as the partial cure, improvement and alleviation of atopic dermatitis symptoms as a result of applying the pharmaceutical composition of the present invention to atopic dermatitis sites.

As used herein, the term "prevention" means that the pharmaceutical composition of the present invention is applied to skin, especially atopic dermatitis, to inhibit or block atopic dermatitis symptoms on the skin, thereby preventing atopic dermatitis from occurring in advance. .

Active ingredient 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane- 6-on

Compound 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl]-used as an active ingredient in the pharmaceutical composition of the present invention 1-oxaspiro [2,5] octan-6-one is represented by Formula 1:

Compound 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2 represented by the formula (1) , 5] octane-6-one is an oxaspiro [2,5] octane derivative as described by Corey (see, eg, Corey EJ, J. Am. Chem. Soc., 1985, 107, 256-257; Corey EJ et al., J. Am. Chem. Soc., 1994, 116, 12109-12110, which may be prepared and obtained by chemical synthesis.

Said 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxanyl] -1-oxaspiro [2,5] octane derivative Oxaspiro [2,5] octane-6-one is described in Corey's article (Corey EJ et al., J. Am. Chem. Soc., 1985, 107, 256-257; Corey EJ et al., J. Am. Chem. Soc., 1994, 116, 12109 to 12110, for use as a pharmaceutical substance and described as an anticancer or immunosuppressive agent. However, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2, 5] Octane-6-one has not been used to treat atopic dermatitis.

The pharmaceutical composition for treating atopic dermatitis according to the present invention is 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxanyl as an active ingredient. ] -1-oxaspiro [2,5] octan-6-one, and the formulation is not specifically limited. For example, ointments, creams, pastes, lotions, liniments, external liquids, tinctures, glycerogelatins, external acids, aerosols, plasters and the like; Detergents such as hair soap, hair rinse and shampoo; And cosmetics such as creams, essences, body lotions, and the like.

Hereinafter, the pharmaceutical composition for treating atopic dermatitis of the present invention will be described in more detail with specific formulation.

4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane-6- Pharmaceutical formulations containing

One aspect of the present invention provides 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro as an active ingredient. Provided is a medicament containing [2,5] octane-6-one to prevent or treat skin conditions caused by atopic dermatitis. The pharmaceutical agent of the present invention is not particularly limited, but may be a transdermal or oral dosage form, and specific examples thereof include ointments, creams, pastes, lotions, liniments, external preparations, tinctures, and glycerogelatins ( glycerogelatins), external acids, aerosols, plasters, capsules, tablets, pills, powders and granules. These formulations are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042 (Chapter 87: Blaug, Seymour), a prescription generally known for all pharmaceutical chemistry.

One formulation of a preferred embodiment of the formulation of the medicament is an ointment. Ointments of the present invention are petrolatum, white petrolatum, yellow ointment, hydrocarbon base such as mineral oil, hydrophilic petrolatum, absorbent base such as anhydrous lanolin, lanolin, cold cream, washable base such as hydrophilic ointment And water-soluble bases such as polyethylene glycol ointment. Their selection and preparation take into account such factors as the rate of release of the drug from the base, the expected increase in percutaneous absorption by the base, whether the skin is sealed by the base, the stability of the drug in the base, and the effect of the drug on the base. But is within the ordinary skill of one skilled in the art of pharmaceutical formulation.

In addition, another formulation of the preferred embodiment of the formulation of the medicament is a cream. Creams of the present invention include W / O forms such as cold creams, emollient creams and O / W forms such as shaving creams, varnishing creams, hand creams, rinsing creams. More preferably it is a varnishing cream which typically contains water and stearic acid. In general, patients or doctors prefer creams to ointments because O / W creams are easier to wash off than ointments. In this regard, the most preferred embodiment of the pharmaceutical formulation of the present invention is creams.

In addition, another formulation of a preferred embodiment of the formulation of the medicament is a lotion. The lotions of the present invention are prepared by methods such as suspensions, emulsions, solutions, and the like, which also belong to those skilled in the art of pharmaceutical formulation. More preferred in the present invention is a white lotion (white lotion), which is prepared by dissolving zinc sulfate (sulfated potash) in purified water separately at 4% and filtering and adding to zinc sulfate solution with gentle stirring at a constant rate.

In addition, another formulation of the preferred embodiment of the formulation of the medicament is a wax. The wax of the present invention can be produced by any of oil-based and ethanol-based, and preferred oil-based oils are less irritating to the skin. In the case of oil-based lubricants, there is a combination of nonvolatile oils such as almond oil, peanut oil, cottonseed oil, volatile oils such as wintergreen and turpentine, or nonvolatile oils.

4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane-6- Cleansing and cosmetic formulations

Another embodiment of the present invention is 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxa as an active ingredient. Provided are cleaning and cosmetics containing spiro [2,5] octane-6-one to prevent or treat skin conditions caused by atopic dermatitis. The pharmaceutical compositions according to the invention can be formulated with a variety of cleaning and cosmetic agents. Representative cleaning and cosmetic agents include, but are not limited to, hair toiletry, hairdressing and skin toyery. Specific examples of these preparations include hair soaps, hair creams, aqueous and aqueous-alcoholic hair lotions, wave-setting lotions (hair fixatives), hairdressing creams and gels, hair sprays, hair tonin, hair oils, hair pomades, hair brills. Leentins, especially hair rinses and shampoos. In addition, examples of skin toys include solid, liquid or powdered soaps and detergent compositions, liquid creams and skin gels, skin oils, body lotions, face lotions, astringents, essences and deodorants (deodorant).

Furthermore, as a preferred embodiment, the compound 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2, 5] The above cleaning and cosmetic formulations containing octane-6-one as an active ingredient comprise an adjuvant of at least one of surfactants, stabilizers, preservatives, wetting agents, anti-inflammatory agents, antioxidants, colorants, water and mixtures thereof. can do. The adjuvant may be present in an amount of 90.0 to 99.999 weight percent based on the total weight of the composition.

Surfactants used in the cleaning and cosmetics of the present invention include both anionic, cationic and amphoteric, and the amount used is typically at least 30% by weight, preferably at least 70% by weight. Selecting and determining the type and amount of surfactant can be easily made by those skilled in the art.

In addition, preferred stabilizers that can be used in the cleaning and cosmetic agents of the present invention include, but are not limited to, glycol stearate. The stabilizer is generally used at 0.1 to 5% by weight relative to the total weight of the composition.

In addition, preferred preservatives that can be used in the cleaning and cosmetic preparations of the present invention include, but are not limited to, tetrasodium ethylenediamine tetraacetic acid (EDTA), 1- (3-chloroallyl) -3,5,7-tra Aza-1-adamantane, parabens, methylparabens, a mixture of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one, phenoxyethanol , Benzyl alcohol, benzophenone-4, methylchloroisothiazolinone, methylisothiazolinone and mixtures thereof. The preservative is generally used at 0.01 to 6% by weight, preferably 0.05 to 4% by weight, more preferably 0.1 to 2% by weight relative to the total weight of the composition.

In addition, preferred wetting agents that can be used in the cleaning and cosmetic preparations of the present invention include wheat protein (eg, lauricmonium hydroxypropyl hydrolyzed wheat protein), hair keratin amino acids, sodium peroxylinecarbolic acid, panthenol, tocopherol (Vitamin E), dimethicone and the like and mixtures thereof. The wetting agent is generally used at 0.01 to 10% by weight, preferably 0.05 to 1.5% by weight, more preferably 0.01 to 1% by weight, based on the total weight of the composition.

In addition, as a colorant that can be used in the cleaning and cosmetics of the present invention FD & C Green No. 3, Ext. D & C Violet 2, FD & C Yellow 5, FD & C Red 40 and mixtures thereof. The colorant is generally used in 0.001 to 0.1% by weight, preferably 0.005 to 0.05% by weight relative to the total weight of the composition.

In addition, anti-inflammatory agents that may be used in the cleaning and cosmetic preparations of the present invention may include any pharmaceutically acceptable compound suitable for topical administration, preferably allantoin. The anti-inflammatory agent is used in an amount sufficient to inhibit or relieve inflammation, and generally 0.01 to the total weight of the composition To 2% by weight, preferably 0.3 to 1.5% by weight, more preferably 0.3 to 1% by weight.

Antioxidants that can be used in the cleaning and cosmetics of the present invention may be used both natural and non-enzymatic antioxidants. Examples of the natural enzyme-type antioxidants include peroxide dismutase (SOD), catalase and glutathione peroxidase. Suitable non-enzymatic antioxidants also include vitamin E (e.g. tocopherol), vitamin C (ascorbic acid), carotenoids, echinacoside and caffeoyl derivatives, oligomeric proanthocyanidins or proantanol (e.g. , Grape seed extract), silymarin (eg, milk thistle extract, silyboom marianium), Ginkgo biloba, green tea polyphenols, and mixtures thereof. The carotenoids are powerful antioxidants, and specific examples thereof include beta-carotene, canthaxanthin, zeaxanthin, lycopene, lutein, crocetin, capxanthine and the like.

In the antioxidant, vitamin E, vitamin C or carotenoids are preferred. In addition, antioxidants are used in amounts sufficient to inhibit or mitigate the effects of free-radicals on the scalp, and are generally used at 0.001 to 1% by weight, preferably 0.01 to 0.5% by weight, based on the total weight of the composition.

On the other hand, cleaning and cosmetics according to the present invention may further contain other auxiliaries commonly used in the art. Examples of such adjuvants include perfumes, dyes (including dyes that simultaneously dye or tint hair), solvents, opacifiers or pearlescent agents (eg esters of fatty acids and polyols, magnesium salts of zinc and zinc salts) , Copolymer dispersions, thickening agents (e.g. sodium chloride, potassium chloride, ammonium chloride and sodium sulfate), fatty acid alkylolamides, cellulose derivatives, natural gums, plant extracts, albumin derivatives (e.g. gelatin), collagen hydrolysis products, natural or synthetic Polypeptides, egg yolks, lecithin, lanolin and lanolin derivatives, fats, oils, fatty alcohols, silicones, diodorants, antimicrobials, antiseborrheic substances, keratinicides (e.g. sulfur, salicylic acid, benzoyl peroxide, selenium sulfide, PG , FA, enzymes) and keratant (eg tar, sulfur, salicylic acid, selenium sulfide, antimicrobial agent, benzoyl peroxide, chlorhexidine, iodine, triclosan, Antifungal agents, enzymes).

Pharmaceutically effective amount

The range of prophylactic or therapeutic doses for atopic dermatitis of the medicaments, detergents and cosmetics according to the invention may vary with severity and formulation. In addition, the frequency of application may also vary depending on the age, weight and constitution of the patient.

Generally, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2 used as an active ingredient in the pharmaceutical composition for treating atopic dermatitis of the present invention. -Oxiranyl] -1-oxaspiro [2,5] octane-6-one is 0.001 to 10% by weight, preferably 0.005 to 2% by weight, more preferably 0.01 to 1% by weight, based on the total weight of the composition It contains. Within this range the concentrations of specific agents are determined by the intended use of them, and certain agents, such as concentrated formulations, which must be diluted prior to use, may contain higher concentrations.

All of the above formulations according to the invention are prepared using 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxy using conventional techniques in the art. Each component, including lanyl] -1-oxaspiro [2,5] octan-6-one, is mixed and the mixture is formulated in the desired form. 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2, 5] Several formulations containing octane-6-one can be used in a conventional manner, preferably applied or massaged to atopic dermatitis.

Preferred Embodiment

The pharmaceutical composition for treating atopic dermatitis according to the present invention is 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxanyl as an active ingredient. ] -1-oxaspiro [2,5] octan-6-one, and the formulation is not specifically limited. For example, ointments, creams, pastes, lotions, liniments, external liquids, tinctures, glycerogelatins, external acids, aerosols, plasters and the like; Detergents such as hair soap, hair rinse, body cleanser and shampoo; And cosmetics such as creams, essences, body lotions, and the like.

Preferred embodiments of the pharmaceutical composition according to the invention are provided as shampoos. The shampoo can be a clear liquid, an opaque liquid, a gel, a cream or a powder. A decisive factor in the interaction of the shampoo with hair and skin or scalp is whether the surfactant that is the base of the shampoo is an anionic, cationic or nonionic surfactant or mixtures thereof. The choice of surfactant can be readily made by one skilled in the art, and in the shampoo compositions of the present invention, the surfactant is typically at least 30% by weight, preferably at least 70% by weight relative to the total weight of the composition.

Examples of anionic surfactants that can be used in the shampoo composition of the present invention include C ₁₀ -C ₂₀ alkylcarboxylates and alkylenecarboxylates, alkylethercarboxylates, fatty alcohol sulfates, fatty alcohol-ether sulfates, alkylols Amide sulfates and alkylolamide sulfonates, fatty acid alkylolamidepolyglycol ether sulfates, alkanesulfonates and hydroxyalkanesulfonates, olefinsulfonates, acyl esters of isethionates, α-sulfo-fatty acid esters, alkylbenzenesulfonates , Alkylphenol glycol ether-sulfonates, sulfosuccinates, sulfosuccinic acid half-esters and diesters, fatty alcohol-ether phosphates, albumin-fatty acid condensation products, alkyl monoglyceride sulfates and sulfonates, alkyl glycerides- Ether sulfonates, fatty acid methyltaurides, fatty acid yarns It includes Cauchy carbonate and sulfonic Poly resorcinol rate. These compounds and mixtures thereof can be used in the form of water-soluble or water-dispersible salts such as sodium, potassium, magnesium, ammonium, monoethanolammonium, diethanolammonium and triethanolammonium and similar alkylolammonium salts.

In addition, examples of suitable cationic surfactants that can be used in the shampoo compositions of the invention include quaternary ammonium salts (eg, di- (C ₁₀ -C ₂₄ alkyl) dimethylammonium chloride or bromide, preferably di- (C _12). -C ₁₈ alkyl) dimethylammonium chloride or bromide); C ₁₀ -C ₂₄ -alkyl-dimethylethylammonium chloride or bromide; C ₁₀ -C ₂₄ -alkyl-trimethylethylammonium chloride or bromide, preferably cetyl-trimethylammonium chloride or bromide and C ₂₀ -C ₂₂ -alkyl-trimethylammonium chloride or bromide; CC-alkyl-dimethylbenzylammonium chloride or bromide, preferably C ₁₂ -C ₁₈ -alkyldimethylbenzylammonium chloride; N- (C ₁₀ -C ₁₈ -alkyl) -pyridinium chloride or bromide, preferably N- (C ₁₂ -C ₁₆ -alkyl) -pyridinium chloride or bromide; N- (CC-alkyl) -isoquinolinium chloride, bromide or monoalkyl-sulfate; N- (CC-alkylolcolaminoformylmethyl) -pyridinium chloride; N- (C ₁₂ -C ₁₈ -alkyl) -N-methyl-morpholinium chloride, bromide or monoalkylsulfate; N- (C ₁₂ -C ₁₈ -alkyl) -N-ethyl-morpholinium chloride, bromide or monoalkylsulfate; C ₁₆ -C ₁₈ -alkyl-pentaoxetylammonium chloride; Diisobutyl-phenoxyethoxyethyldimethylbenzylammonium chloride; Salts of N, N-diethylaminoethyl-stearylamide and -oleylamide with hydrochloric acid, acetic acid, lactic acid, citric acid and phosphoric acid; N-acylamidoethyl-N, N-diethyl-N-methylammonium chloride, bromide or monoalkyl-sulfate and N-acylamidoethyl-N, N-diethyl-N-benzylammonium chloride, bromide or mono Alkyl-sulfates, where acyl is preferably stearyl or oleyl.

In addition, nonionic surfactants in the shampoo compositions of the present invention can be used with adjuvants because of their low foaming power. Representative nonionic surfactants include, but are not limited to, lyophilic high molecular weight esters of aliphatic polyhydric alcohols and aliphatic polycarboxylic acids and polyglycol esters of fatty acids. Examples thereof include fatty alcohol ethoxylate (alkylpolyethylene glycol); Alkyl phenol polyethylene glycols; Alkyl mercaptan-polyethylene glycol; Fatty amine ethoxylates (alkylamine-polyethylene glycols); Fatty acid ethoxylates (acid-polyethylene glycol); Fatty acid ethoxylates (acid-polyethylene glycol); Polypropylene glycol ethoxylate (Pluronic ^® ); Fatty acid alkylolamides (fatty acid amidepolyethylene glycols); Sucrose esters; Sorbitol esters and polyglycol ethers.

In addition, examples of amphoteric surfactants that can be used in the shampoos of the present invention are the alkali metal salts and N- (C ₁₂ -C ₁₈ -alkyl) -β-aminoprop as mono-, di- and tri-alkylolammonium salts. Cypionate and N- (C ₁₂ -C ₁₈ -alkyl) -β-iminodipropionate; N-acylamidoalkyl-N, N-dimethylacetobetaine, preferably N- (C ₈ -C ₁₈ -acyl) -amidopropyl-N, N-dimethyl-acetobetaine; C ₁₂ -C ₁₈ -alkyldimethyl-sulfopropyl-betaine; Imidazoline type amphoteric surfactants (e.g. Miranol ^® or Steinapon ^® ), preferably 1- (β-carboxy-methyloxyethyl) -1- (carboxymethyl) -2-lauryl-amida Zolinium; Amine oxides such as C ₁₂ -C ₁₈ -alkyldimethylamine oxides and fatty acid amido-alkyl-dimethylamine oxides. The cationic surfactant may also be present in other agents such as, for example, hair rinses, hair tonics and hair repellents and anhydrous oily agents (eg hair oil, hair pomade and hair brilliantine).

In addition, the shampoo compositions of the present invention contain blowing agents such as fatty acid mono- and di-alkanolamides. Wherein the fatty acid mono-and di-alkanoic Examples of the all-amides cocamide MEA [formula _{R-CO-NHCH 2 CH 2} OH ( wherein, R represents the residue after removal of carboxyl group of coconut fatty acids), coconut acid monoethanol amide Mixtures of], cohydride DEA [mixture of diethanolamides of the formula R-CO-N (CH ₂ CH ₂ ON), wherein R is as defined above], oleamide MEA and oleamide DEA. have.

In addition, the shampoo composition of the present invention contains a thickener for imparting a viscosity to the formulation in the range of about 4,000 to about 9,000 cps at room temperature. Such thickeners include Carbopol 1342, a copolymer of sucrose allyl ether and C _10-30 alkyl acrylate, acrylic acid and / or methacrylic acid. Other thickeners that may be used include cellulose derivatives such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose and the like. The addition of small amounts of salts (NaCl) also serves to control the viscosity of the final formulation and is added in an amount of 0.25 to 0.6% by weight.

In addition, the shampoo composition of the present invention contains fragrances, colorants, opacifiers, conditioners (e.g., polyquaternary salts 7 [polymeric quaternary ammonium salts of acrylamide and dimethyl diallyl ammonium chloride]) which are standard shampoo formulations, and the like. can do.

In addition, the shampoo compositions of the present invention contain acids, bases and buffers as necessary to maintain the pH at 4-10, preferably 6.5-8, more preferably 6.9-7.4. Neutral pH is preferred to minimize latency to skin sensitization, and the nature and mode of use of such pH adjusting materials are well known in the art.

The invention will be more specifically illustrated by the following examples. The following example shows compound 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5 ] Toxicity Test of Octan-6-one and 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxa The preparation of a formulation containing spiro [2,5] octane-6-one as an active ingredient is exemplified. However, the present invention is not limited only to the following examples.

4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2 used in the present invention below , 5] octane-6-one is termed 'oxaspiro [2,5] octane-6-one'.

[Test Example 1] 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2] in vivo , 5] pharmacological efficacy test of octane-6-one

1-1. Antipruritic Effect in Animal Model of Atopic Dermatitis

The subjects of this experiment were BALB / C mice weighing 20-30mg and healthy, mature Sprague-Dawley rats weighing around 250-300mg. These experimental animals were fed in a quiet atmosphere, with tap water and pellet feed (Jeong Feed Co., Ltd. Daejeon), being careful not to stress as much as possible. Atopic dermatitis in mice was induced by injection of 50 μl of compound 48/80 (50 μg / ml) into the dermal dermis of the dorsal neck of the mouse (Orito K et al., A new analytical system for quantification scratching behavior in mice, Br J Dermatol, 150 (1), 33-8, 2004). The atopic dermatitis animal model was evaluated by video recording the mouse's behavior for 60 minutes after 48/80 injections of Compound. Furthermore, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane- To test the pharmacological efficacy of 6-one atopic dermatitis, various concentrations of 4-hydroxy-5-methoxy-4- [2-methyl-3- (6) diluted in oil for 6 days prior to compound 48/80 injection 50 μl of 3-methyl-2-butenyl) -2-oxanyl] -1-oxaspiro [2,5] octane-6-one twice a day (12 times in total) is applied to the dorsal neck of the mouse It was. The mouse was observed to scratch the neck with the forefoot, and counted the number of times to determine the presence and extent of skin itching (pruritus). The results are shown in Figures 1a to e below.

As can be seen in Figures 1a to e below, the number of scratching the neck with hind feet after injection of compound 48/80 into the skin was about 30-40 times per 10 minutes in the first 30 minutes, but decreased over time. It became. However, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane- 6-on pretreatment (applied to the skin), the number of scratches of the neck with hind paws by compound 48/80 was 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2- It was confirmed that butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane-6-one was significantly reduced in a concentration dependent manner. As a result of the above 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] Octane-6-one was found to be effective in inhibiting atopic dermatitis (skin pruritus) induced by compound 48/80.

1-2. Histological Observation of Skin in Animal Model of Atopic Dermatitis

Induce atopic dermatitis by injecting Compound 48/80 into the skin behind the mouse's neck as in 1-1 above, and then, after 1 hour, sacrifice the observed mouse to cut off the skin at the site of inflammation. Fixed in formalin. After preparing paraffin sections having a thickness of 5 μm by a conventional method, HE, congo red, and toluidine blue staining were performed to determine the degree of inflammatory cell infiltration and degranulation of mast cells in the inflammatory site. Observation was made using a microscope and photographs were taken (see Sailstad DM et al., A murine model for low molecular weight chemicals: differentiation of respiratory sensitizers (TMA) from contact sensitizers (DNFB), Toxicology 15, 194, 147-61, 2003). ).

A) Observation of multinucleated leukocytes in the skin

The skin tissue of the mouse was prepared by paraffin sections having a thickness of 5 μm in a conventional manner, subjected to H-E staining, and photographed by observing the degree of infiltration of polymorphic nuclear leukocytes (PMNL) with an optical microscope. The results are shown in FIG. 2.

As can be seen in Figure 2, the compound 48/80 injection was observed in the infiltration of a large number of multinucleated leukocytes in the skin causing atopic dermatitis, it can be seen that the inflammatory response is induced (Fig. 2-a), 4-hydr Pretreatment of oxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octan-6-one (Applied to the skin) it was found that the infiltration of multinucleated leukocytes by compound 48/80 was significantly suppressed (Fig. 2-b). 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane from the above 6-one was found to have an effect of inhibiting the infiltration of multinucleated leukocytes by compound 48/80.

B) Observation of coral white blood cells in the skin

The skin tissue of the mouse was prepared by congo red staining by preparing paraffin sections having a thickness of 5 μm in a conventional manner, and photographed by observing the degree of infiltration of coral leukocytes (eosinophils) with an optical microscope. The results are shown in FIG. 3.

As can be seen in Figure 3 below, infiltration of many white blood cells was not observed in the skin induced by atopic dermatitis with compound 48/80 injection (Figure 3-a), 4-hydroxy-5-methoxy 4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octan-6-one was pretreated (applied to the skin) Even when compound 48/80 was injected, no infiltration of coral leukocytes was observed (Fig. 3-b). Therefore, infiltration of multinucleated leukocytes in atopic dermatitis by compound 48/80 was considered to be mesenchymal leukocytes, and coral leukocytes would not be involved.

C) Observing mast cells from the skin

Paraffin sections of 5 μm thickness were prepared by the conventional method, and toluidine blue staining was performed. Mouse microscopic observations were performed by observing the degree of infiltration and degranulation of mast cells. . The results are shown in FIG. 4.

As can be seen in Figure 4, many of the degranulated mast cells were observed in the skin induced by atopic dermatitis by compound 48/80 injection (Fig. 4-a), 4-hydroxy-5-methoxy-4- Pretreatment of [2-methyl-3- (3-methyl-2-butenyl) -2-oxiranyl] -1-oxaspiro [2,5] octan-6-one (applied to skin) compound 48 / Degranulation of mast cells by 80 was significantly inhibited (Fig. 4-b). Therefore, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane- 6-on was found to have an effect of inhibiting degranulation of skin mast cells by compound 48/80.

[Test Example 2] 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2 in a test tube , 5] inhibition of mast cell activity of octane-6-one

2-1. Cytotoxicity Experiment

4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl- using 3- (4,5-dimethylthiazol-2yl) -2,5-diphenyltetrazolium bromide (MTT) 2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octan-6-one was checked for cytotoxicity. Living cells form MTT crystals by the mitochondrial enzyme succinate dehydrogenase.

First, Cochrane and Douglas's method was modified and used to purely separate celiac mast cells (Cochrane DE. Et al., Proc. Natl. Acad. Sci., 1974, 71, 408). That is, about 10ml of Ca-Locke solution (150mM NaCl, 5mM KCl, 2mM CaCl ₂ , 1.0mg / ml bovine serum alvumin, 1.0mg / ml glucose, 0.1mg / ml heparin, pH7.4) was injected into the rat abdominal cavity. The abdominal wall was massaged for 90 seconds to obtain an abdominal cavity washing solution. After the abdominal lavage fluid was immersed, the supernatant was discarded and resuspended with the same Ca-Lock solution. Put 3.5 ml of isotonic percoll solution (10 x Hank's solution 1ml + percoll 9ml) into a 15ml centrifuge tube, carefully place 0.75ml of mast cell suspension, and fill 0.5ml of Ca-Locke solution with the upper layer. After standing still, centrifuged for 15 minutes at 125xg. 2 ml of the supernatant was removed by pipette and washed twice with Ca-Locke solution at 4 ° C to obtain pure mast cell suspension.

Next, peritoneal mast cells (2 × 10 ⁵ cells / 0.2ml) were harvested to control only HEPES-Tyrode (25 μl) or 4-hydroxy-5-methoxy-4- [2-methyl at various concentrations. -3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octan-6-one was treated and incubated at 37 ° C. for 4 hours. After incubation, 50 µl of 1 mg / ml MTT was added, and the mixture was reacted at 37 ° C for 1 hour, followed by centrifugation. After melting the crystals using dimethyl sulfoxide, the absorbance was measured at 570 nm using a spectrophotometer (Spcetra MAX plus, Molecular Devices, USA), and the absorbance of HEPES-Tyrode-treated peritoneal mast cells was measured. The survival rate was calculated by converting the change of absorbance into a percentage as time passed to 100. The results are shown in FIG. 5.

As can be seen in FIG. 5, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxa Spiro [2,5] octane-6-one confirmed that no cytotoxicity was observed, similar to the control.

2-2. Pure separation of mast cells

Cochrane and Douglas's method (Cochrane et al., Calcium-induced extrusion of secretory granule (exocytosis) in the mast cells exposed to 48/80 or the ionopores A23187 and X-537A, Proc. Natl. Acad. Sci. USA, 71 , 408, 1974). About 10ml of Ca-Locke solution (150mM NaCl, 5mM KCl, 2mM CaCl ₂ , 1.0mg / ml bovine serum albumin, 1.0mg / ml glucose, 0.1mg / ml heparin, pH7.4) was injected into the rat abdominal cavity. The abdominal wall was massaged for 90 seconds to obtain an abdominal lavage fluid. After the abdominal lavage fluid was centrifuged, the supernatant was discarded and resuspended with the same Ca-Lock solution. Next, 3.5 ml of isotonic percoll solution (10 x Hank's solution 1ml plus percoll 9ml) was added to a 15ml centrifuge tube, and then 0.75ml of the mast cell suspension was carefully placed, followed by Ca-Locke. 0.5 ml of the solution was charged to the upper layer, allowed to stand for 10 minutes, and then centrifuged at 125 xg for 15 minutes. 2 ml of the supernatant was removed by pipette and washed twice with Ca-Locke solution at 4 ° C to obtain pure mast cell suspension.

2-3. Mast Cell Activation Mechanism

The activation of mast cells is largely caused by three kinds of stimuli. First, antigen, anti-IgE, and lectin are cross-linked to IgE attached to the Fc receptor of mast cells (Fc). by pharmacological compounds such as receptor-mediated triggering, compound 48/80, calcium ionophore, melittin, and third, anaphylatoxins such as C3a and C5a. Activation of mast cells. Mast cells activated by a variety of stimuli, the intracellular calcium concentration increases, cAMP level decreases through the signal transmission process, the degranulation of mast cells occurs. When mast cells are activated, histamine, proteolytic enzymes, heparin, and chemotactic factors, which are already formed in the mast cell granules, are released, and phospholipase A ₂ is activated in the cell membrane to prosta Newly synthesized materials such as prostaglandin, leukotriens, and thromboxans are liberated. Various mediators released from mast cells cause increased vascular permeability, edema, pruritus, and broncho smooth muscle contraction, resulting in various allergic symptoms.

Thus, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane- After pretreatment of 6-one to mast cells, the compound 48/80, a mast cell active substance, was treated to determine the degranulation of mast cells, the amount of histamine released, calcium influx, and cAMP levels. ] Octan-6-one inhibited mast cell activation and its pharmacological mechanism was examined.

관찰 Degranulation observation of mast cells on inverted microscope

180 μl of the resuspended mast cell suspension of 2-2 was placed in an inverted microscope chamber and allowed to stand for 10 minutes at room temperature to allow cells to precipitate. Degranulation with compound 48/80 was carried out by 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [ To determine whether 2,5] octane-6-one is inhibited, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2 at various concentrations After pretreatment with -oxanyl] -1-oxaspiro [2,5] octane-6- warm solution for 10 minutes, compound 48/80 was added and the morphological changes of mast cells were observed under a magnification of 1,000 times. The results are shown in FIG. 6.

As can be seen in Figure 6, it was confirmed that inhibiting mast cell degranulation by compound 48/80.

측정 Determination of histamine release from mast cells

Harvima's method (see: Harvima RJ, Optimization of histamine radiolenzymatic assay with purified histamine N-methyltransferase, Clinica Chimica Acta, 171, 247, 1998) was used. To 180 μl of mast cell suspension (10 ⁶ cells / ml) isolated by the above-described mast cell pure separation method, Locke solution, compound 48/80, or 4-hydroxy-5-methoxy-4- [ Histamine liberated from mast cells by adding 20 μl of a 2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octan-6-one solution The amount was measured. In addition, the histamine glass by the compound 48/80 was added to 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1- To determine whether oxaspiro [2,5] octane-6-one is inhibited, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl After pretreatment with) -2-oxiranyl] -1-oxaspiro [2,5] octane-6-one solution, compound 48/80 was added to determine the amount of histamine by radioisotope enzymatic assay. Measured. The results are shown in FIG. 7.

4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] Octan-6-one was confirmed to inhibit histamine release from mast cells by compound 48/80.

측정 Measurement of calcium concentration in mast cells

Foreman's method (Foreman JC et al., Calcium ionophores and movement of calcium ions following the physiologic stimulus to a secretory process, Nature (London), 245, 249, 1973) was used. Mast cells purely isolated by the method described above were resuspended in calcium free phosphate buffer solution containing 8μCi ⁴⁵ Ca / ml. Compound 48/80 in 180 μl mast cell suspension, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxanyl] 20 μl of -1-oxaspiro [2,5] octane-6-one was added to measure the amount of calcium introduced from mast cells. In addition, calcium influx by compound 48/80 was also observed in 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-. To determine if oxaspiro [2,5] octane-6-one was inhibited, pretreated with various concentrations of oxaspiro [2,5] octane-6-one solution for 10 minutes and then added compound 48/80 to 30 The reaction was carried out for a minute and the calcium amount was measured. After reacting for quantification of calcium, the supernatant was discarded and washed three times with ₃ ml of 1 mM LaCl ₃ . Next, put the cell pellet (pellet) 10μl Triton-X 150μl to destroy the mast cells, add 2ml of the cocktail solution (cocktail solution) and then use a beta scintillation counter (beta-scintillation counter) The amount of calcium introduced into the body was measured. The results are shown in FIG. 8.

As can be seen in Figure 8, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxa Spiro [2,5] octane-6-one was found to inhibit calcium influx into mast cells by compound 48/80.

측정 cAMP measurement in mast cells

After separation by the pure mast cell separation method described in 2-2 above, the cell number was adjusted to 1 × 10 ⁶ cells / ml of the mast cells in suspension, and 200 μl was obtained therefrom. To change the cAMP level of mast cells, 180 μl of mast cell suspension was added compound 48/80 and 20 μl of various concentrations of oxaspiro [2,5] octane-6-one solution. In addition, cAMP levels by compound 48/80 were determined to be 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1- To determine whether oxaspiro [2,5] octane-6-one is varied, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) at various concentrations After pretreatment with -2-oxalanyl] -1-oxaspiro [2,5] octane-6-one for 10 minutes, compound 48/80 was added to react for 30 minutes, and cAMP levels were measured. To stop all reactions, discard the supernatant after centrifugation, add 0.25 ml of 50 mM acetate buffer (pH 6.2), freeze the cells rapidly with liquid nitrogen, and then cut for 10 minutes in 100 ℃ water. After that, 100 μl of the supernatant was obtained for cAMP quantification. cAMP quantification is a cAMP [ ¹²⁵ I] radioimmunoassay kit (Du Pont) based on the principles of Holmegaard (Holmegaard SN, Measurement of cAMP in clinical investigations, Acta. Endocrinologica, 101, 1, 1982). Company, Wilmington, DE) was measured as follows.

100 μl of the working tracer solution (cAMP [ ¹²⁵ I] -Tracer: cAMP Carrier serum = 1: 1 (v / v)) was added to 100 μl of the supernatant obtained above and mixed well. After reacting for an hour, 0.5 ml of cAMP precipitator was added and mixed, and then centrifuged at 1,200 xg for 15 minutes. Next, the supernatant was discarded and measured by γ-counter (COBRA II, Auto GAMMa, A canberra company, Australia). The results are shown in FIG. 9.

As can be seen in Figure 9 below, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxa Spiro [2,5] octane-6-one was found to increase the level of cAMP in mast cells, thereby inhibiting the decrease in mast cells by compound 48/80.

4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl)-using an atopic dermatitis animal model according to compound 48/80 of Test Examples 1 and 2 above. The following results were obtained from a study to determine whether 2-oxiranyl] -1-oxaspiro [2,5] octane-6-one is effective in the treatment and prevention of atopic dermatitis.

① 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane-6 -On inhibited the concentration of atopic dermatitis pruritus caused by compound 48/80.

② Infiltration of inflammatory cells (leukocytes) and skin mast cell degranulation in atopic dermatitis by Compound 48/80 are 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2 -Butenyl) -2-oxiranyl] -1-oxaspiro [2,5] octan-6-one was reduced by pretreatment (skin application).

③ 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane-6 -ON inhibited degranulation of mast cells by compound 48/80.

④ 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane-6 -On inhibited the histamine release of mast cells by compound 48/80.

⑤ 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane-6 -ON inhibited the calcium influx of mast cells by compound 48/80.

⑥ 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane-6 -On inhibited the activation of mast cells by compound 48/80 by increasing the level of cAMP in mast cells.

From the above results, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] Octane-6-one was confirmed to have a pharmacological effect of reducing the inflammatory response by inhibiting infiltration and mast cell degranulation of inflammatory cells in atopic dermatitis animal model. This pharmacological effect is thought to inhibit the histamine release and degranulation from mast cells by increasing the cAMP level of mast cells and blocking intracellular calcium influx. Therefore, the 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane -6-one may be useful for the prevention and treatment of allergic immune diseases including atopic dermatitis caused by activation of mast cells.

[Test Example 3] 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5 Percutaneous toxicity test of Octane-6-one

4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxiranyl] -1-oxaspiro [2, purified from the culture filtrate. 5] Acute dermal toxicity test in octane-6-one rats (magnetic, 4 week old) was conducted in accordance with KFDA standards. In the test method, the hairs of the rats were shaved, and then uniformly applied at a concentration of 4000 mg / kg (body weight) to about 10% of the body surface area and observed for 15 days.

As a result, skin irritation such as skin erythema and skin formation was not seen. Thus, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane- 6-one was determined to be a low toxicity antifungal substance.

Example 1 Shampoo Formulation for Normal Hair

To prepare a shampoo with the components of Table 1. 1.64% stock solution of Carbopol 1342 (made by dividing the polymer powder evenly using a Quadro dispenser into the water vapor by vacuum) and deionized water were added and heated to about 70 ° C. Sodium laureth sulfate and sodium cocoyl sarcosinate, which are surfactants, are added, followed by adding blowing agent cocamide MEA and pearlescent ethylene glycol distearate and mixing until complete dissolution. Next, the solution is slightly cooled and the active ingredient is 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxanyl] -1 -Oxaspiro [2,5] octane-6-one (hereinafter referred to as "oxaspiro [2,5] -6-one") was added with stirring. The temperature of the solution was then adjusted to 40 ° C. and the conditioner polyquaternium-7, preservative quater salt-15 and tetrasodium EDTA, colorants and fragrances and for the increase of the solution NaCl was added. To the solution was added a 25% aqueous NaOH solution to adjust the pH to 6.9 to 7.4, followed by the addition of deionized water at the final volume to obtain a shampoo.

ingredient Content (% by weight) Oxaspiro [2,5] -6-one 1.0 Sodium laureth sulfate 30 Sodium cocoyl sarcosinate 10 Cocamide MEA 4.0 Ethylene Glycol Distearate 1.25 Poly Quaternary Salt-7 1.0 Carbopol 1342 0.6 Tetrasodium EDTA 0.5 Aroma oil 0.5 Sodium chloride 0.3 Sodium Hydroxide 25% 0.92 Quaternary Salt-15 0.05 coloring agent 0.001 Deionized water Remaining amount

Example 2 Shampoo Formulation for Dry or Damaged Hair

To the composition of Table 2 to prepare a shampoo formulation for dry or damaged hair in the same manner as in Example 1.

ingredient Content (% by weight) Oxaspiro [2,5] -6-one 1.5 Sodium laureth sulfate 30 Sodium cocoyl sarcosinate 10 Cocamide MEA 4.0 Glycol distearate 1.25 Poly Quaternary Salt-7 5.0 Carbopol 1342 0.5 Tetrasodium EDTA 0.5 Aroma oil 0.5 Sodium chloride 0.4 Sodium Hydroxide 25% 0.733 Quaternary Salt-15 0.05 coloring agent 0.0018 Deionized water Remaining amount

The proportion of sodium hydroxide in the shampoo formulations prepared in Examples 1 and 2 may vary slightly to adjust to the desired pH level of 6.9 to 7.4, and the proportion of sodium chloride may also vary slightly to make the desired viscosity.

Example 3 Hairdressing Formulation

To the hair dressing was prepared by mixing the ingredients in Table 3 in a container.

ingredient Content (% by weight) Oxaspiro [2,5] -6-one 1.3 Light mineral oil 72.0 Isopropyl myristate 22.0 lanolin 2.0 Lanolin esters 1.5 Spices 1.2

Example 4 Hydrophilic Ointment

To prepare a hydrophilic ointment washed with water with the components of Table 4 below. First, stearyl alcohol and white petrolatum were dissolved in a steam bath and warmed to about 75 ° C. Separately water was heated to 75 ° C., to which sodium lauryl sulfate, propylene glycol, methylparaben and propylparaben were added. 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane as an active ingredient Ointment was obtained by adding -6-one and stirring until condensation.

ingredient Content (% by weight) Oxaspiro [2,5] -6-one 1.5 White Petrolatum 25 Stearyl alcohol 25 Propylene glycol 12 Sodium lauryl sulfate 1.0 Methylparaben 0.025 Propylparaben 0.025 Purified water Remaining amount

Example 5 Cream Formulation

To prepare the O / W cream with the ingredients in Table 5. The oil phase and the aqueous phase were separately heated to 70 ° C., then the oil phase was added slowly to the aqueous phase to form a crude emulsion with stirring. The emulsion was then cooled to about 55 ° C. and homogenized. Cooling with shaking until the homogenate condensed gave a cream.

ingredient Content (% by weight) Oil phase Oxaspiro [2,5] -6-one 1.5 Stearyl alcohol 15 beeswax 8 Sorbitan monooleate 1.25 Aqueous phase Sorbitol Solution, 70% USP 7.5 Polysorbate 80 3.75 Methylparaben 0.025 Propylparaben 0.015 Purified water Remaining amount

Example 6 Varnishing Cream Formulation

A varnishing cream was prepared using the ingredients shown in Table 6 below. First, the oil phase and the aqueous phase were separately heated to about 65 ° C. The oil phase was then added slowly to the aqueous phase to form a crude emulsion with stirring. The emulsion was then cooled to about 50 ° C. and homogenized. Cooling with shaking until the homogenate condensed gave a varnishing cream.

ingredient Content (% by weight) Oil phase Oxaspiro [2,5] -6-one 1.5 Stearic acid 13 Stearyl alcohol 1.0 Cetyl alcohol 1.0 Aqueous phase glycerin 10 Methylparaben 0.1 Propylparaben 0.05 Potassium hydroxide 0.09 Purified water Remaining amount

Example 7 Gel Formulation

To prepare a gel (lubricationg jelly) to the components of Table 7. First, dissolve Methocel 90 HC 4000 in 40 ml of hot (80 ~ 90 ° C) water. The solution was prepared by dispersing and cooling in a refrigerator overnight. Separately, Carbopol 934 was dispersed in 20 mL of water, the pH was adjusted to 7.0 by addition of a sufficient amount of 1% sodium hydroxide solution and purified water was added to make a volume of 40 mL. In addition, methylparaben and 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2, 5] octan-6-one was dissolved in propylene glycol. The three solutions prepared above were mixed with care to avoid entering air to obtain a gel.

ingredient Content (% by weight) Oxaspiro [2,5] -6-one 1.5 Methocel 90 H.C. 4000 0.8 Carbopol 934 0.24 Propylene glycol 16.7 Methylparaben 0.1 Sodium hydroxide pH adjustment Purified water Remaining amount

[Test Example 4] Skin irritation test

The skin irritation test in the present invention was performed with reference to a paper published by Genji Imokawa et al., And a closed patch test using a Finn Chamber of Norgesplaster A / S was conducted. .

The preparations prepared in Examples 1 to 7 were absorbed by 10 μl in a paper disc fitted with a Finn Chamber, and placed in a Finn Chamber for 48 hours on 10 adult male skins. . After 48 hours, the Finn Chamber was immediately removed, washed with running tap water and dried, and after 2 hours, the condition of the skin was determined according to the following criteria. The results are shown in Table 8 below.

Judgment criteria (stimulation intensity)

-: No change with the naked eye

±: light redness

+: Moderate redness

++: strong redness and edema

Test subject Stimulation degree Example 1 - Example 2 - Example 3 - Example 4 - Example 5 - Example 6 - Example 7 -

As can be seen in Table 8, the transdermal formulation of the present invention was shown to be non-toxic at all by not irritating the skin.

<Test Example 5>

Subjects were selected as male / female (including infants and adolescents) aged 4 to 30 years with atopic dermatitis. They should keep their lifestyle and skin care the same 2 weeks before their first visit, and then determine whether they have atopic dermatitis through physical examination, questionnaire and clinical evaluation by dermatologist according to Hanifin & Rajka's diagnostic criteria. Subjects were selected and the basic information is shown in Table 9. In addition, the composition of the subject, atopy symptom classification, the classification by the occurrence symptoms are shown in Table 10-12. Most of these patients suffered from dryness, lichen dermatitis, and couch scars, and in some cases edema or papules were observed, and the lesions were often scraped with exudation or crusting.

Human test studies were tested in the following manner.

First, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane- The product of Example 6 containing 6-on was applied twice a day to the whole body, and after taking a shower with lukewarm water, the water was removed and applied to the atopic dermatitis site within 5 minutes. The test period per subject of the human test was 2 weeks, before the product use (0 week), 1 week, 2 weeks after the use of the dermatologist's visual evaluation and non-invasive measuring equipment and subject self-evaluation evaluation method is carried out The effectiveness of the product was evaluated.

At the first visit, the subject waited for 30 minutes in a designated place of constant temperature and humidity conditions (temperature 22 ± 2 ℃, humidity 45 ± 5%) and judged the severity of atopic dermatitis according to the SCORAD Index criteria. Water loss and skin acidity (pH) were measured. In addition, a dermatologist selected the most severe lesion of atopic dermatitis and took a photograph (Pro 14n, KODAK, USA). The severity of atopic dermatitis was evaluated at the same method conditions as at the start of the test by visiting the product for 1 week and 2 weeks after use. During the human body test period, the same lifestyle and skin care as before the start of the test was kept the same as before the product was used. Only the products received until the end of the human body test were used and all cosmetics were not applied on the day of measurement.

Details of the evaluation method are as follows.

1) Visual evaluation of dermatologist using SCORAD Index (SCORing Atopic Dermatitis)

The degree of atopic dermatitis in the subject was assessed by the dermatologist (KNS or MTK) with the SCORAD Index (see European Task Force on Atopic Dermatitis, Severity scoring of atopic dermatitis, The SCORAD Index, Dermatology, 1993, 186, 23--). 31). The SCORAD Index is a scorecard that measures the severity of atopic disease. The composition and criteria of SCORAD Index are as follows.

The SCORAD Index consists of three subscores:

A) A (area score based on body surface area)

A; Area score

= SUM

B) B (severity score based on six symptoms found in atopic dermatitis)

B; Severity Score

= SUM (score of 6 criteria)

Note: The severity was based on the average severity of the body parts where atopic dermatitis is typically observed.

C) subjective symptoms

C; Subjective Symptoms of Pruritus and Sleep Deprivation

= (Score of pruritus from 0 to 3) + (Score of lack of sleep from 0 to 3)

Note: Pruritus and sleep deprivation were graded on a visual continuity scale scale ranging from 0 to 3. Severity was based on average for three days before the test.

D) total

Using a) to c), the final result was calculated according to the following formula.

SCORAD Index = (A / 5) + (7 × B / 2) + C

2) SCORAD Index Details

A) Visual evaluation, clinical characteristics and clinical history by dermatologist

The same examiner visually assesses the degree of symptoms from 0 to 3 points for each of the 11 symptom areas for 6 symptoms at 0, 1 and 2 weeks. Is indicated. In addition, the onset period was confirmed at the beginning of the initial test, and the presence of accompanying diseases (asthma, rhinitis, etc.) was checked. The symptoms of pruritus (itch) and insomnia during the 3 days prior to the visit were evaluated by a dermatologist.

6 symptoms

(1) erythema

(2) oozing or crusting

(3) edema or papulations

(4) dryness

(5) lichenification

(6) sofa bed (excoriation)

The assessment of six symptoms was assessed from 0 to 3 with the most severely injured areas selected for each assessment of criteria.

-11 symptoms

(1) feet

(2) knees

(3) legs

(4) hands

(5) arms

(6) face

(7) neck

(8) scalp

(9) buttocks

(10) belly and chest, anterior aspect of trunk

(11) posterior aspect of trunk

-Degree of symptoms (severity)

0 points: No symptoms: none

1 point: mild symptoms (mild): mild

2 points: severe symptoms (severity): severe

3 points: symptoms are very severe (severe): extremely severe

Subject Basic Information Number name age gender One KKY 12 F 2 KDY 10 M 3 KMS 23 F 4 KSM 4 F 5 KYJ 26 F 6 KHB 6 F 7 GHJ 6 F 8 MYJ 8 F 9 PWY 12 M 10 PJS 8 M 11 SHK 20 F 12 SDS 16 F 13 SEA 6 F 14 SYC 6 M 15 YKY 19 M 16 LSB 11 F 17 LSA 16 F 18 LJM 7 M 19 JBW 21 F 20 JJK 23 M Average 13.00 Standard Deviation 6.94

The composition of the subject Subject Information Classification Target ratio (%) gender man 7 35.0 Woman 13 65.0 age 4 years old to 10 years old 8 40.0 10 years old to 20 years old 7 35.0 20 years old to 30 years old 5 25.0

Atopic Symptoms Classification Atopic Symptoms Classification Target ratio (%) Onset period Less than 6 months 3 15.0 6 months to 2 years 2 10.0 2 to 5 years 7 35.0 More than 5 years 8 40.0 Initial symptom degree Mild 6 30.0 Severe 14 70.0 Cardiac 0 0 Main symptom area Face, neck, scalp 6 30.0 Arms and hands 17 85.0 Knee, leg, foot 24 120.0 Back, chest, belly 8 40.0 hip 4 20.0 Accompanying diseases asthma 0 0.0 Rhinitis 5 25.0 Heat 4 20.0

Classification by occurrence of dermatologist's visual evaluation Symptom Target ratio (%) Hong Van 3 15.0 Effusion or crust 3 15.0 Edema or papules 3 15.0 dry 19 95.0 Taesun 15 75.0 Sofa 8 40.0

B) Atopic improvement effect by subject's self-assessment

At the first visit, subjects self-assessed with a scale of 0 to 3 below 3 days before the visit to the Institute for pruritus and insomnia symptoms in subjects 1 and 2 weeks after use of the product, respectively. The guardian).

Severity of symptoms

0 points: No symptoms: none

1 point: mild symptoms (mild): mild

2 points: severe symptoms (severity): severe

3 points: symptoms are very severe (severe): extremely severe

3) Instrumental measurement

The non-lesion site was selected and TEWL (Trans Epidermal Water Loss), skin moisture content (capacitance), and pH were measured at the 0, 1, and 2 week visits. One severe and representative symptom site was selected and measured.

The above results were summarized and shown in FIGS. 10 to 15.

As can be seen in FIG. 10, the dermatologist's visual evaluation of the six symptoms showed the most improvement of the thyroid disease after 1 week of product use, compared to 0 weeks, and exudation or peeling, edema / papules, erythema, and sores. It showed a tendency to improve in order of drying. In addition, as a result of visual evaluation by the dermatologist for six symptoms, the exudation or crust was most improved after 2 weeks, and the sensitization and edema / palpation were also improved compared to before use. In addition, cures, dryness and erythema symptoms were also improved, and the symptoms improved overall.

In addition, as shown in Figure 11 below, the test product from the results of a one-week human test on the product using the SCORAD INDEX, which is calculated by combining the results of the naked eye and the subject's self-assessment by a dermatologist It was found to help the improvement of about 19.9% and to improve the improvement of about 46.6% after two weeks of product use.

In addition, as shown in FIG. 12, a questionnaire evaluation was conducted on how much atopic improvement effects the subjects felt. As a result, pruritus helped improve about 21.7% compared to 0 weeks after the test. 2 weeks later, they responded by helping to improve about 43.5%. In addition, in the case of insomnia, 1 week after the test helped to improve about 20.0% compared to 0 weeks, it was confirmed that 2 weeks later also answered about 60.0% to help improve.

Meanwhile, according to a recently published research paper, transdermal water evaporation was reported to be 50 to 150% higher than in the general population (see Comparison of Transepidermal Water Loss, Capacitance and pH Values in the Skin between Intrinsic and Extrinsic Atopic). Dermatitis Patients, J. Korean Med Sci., 2003, 18, 93-6). As can be seen in Figure 13 below, even in this human test using TEWAMETER (TM 300, Courage & Khazaka, Germany), the lesion area is about 21.80 ± 12.05 g / m ² h on average, 13.35 ± for non-lesion A result of 7.13 g / m ² h could be observed. However, after one week of use of the test product, the results of transdermal moisture evaporation in the lesions before and after using the product showed a decrease of 7.9% and 4.8% of the non-lesioned cases. In addition, after 2 weeks, the lesion was decreased by 12.9% and the non-lesion was increased by 9.0%.

On the other hand, according to a recently published research paper on skin moisture retention, atopy patients reported having water retention of up to 25% less than that of normal people. As can be seen from the results of FIG. 14 below, in the case of this test using a Corneometer (CM825, Courage & Khazaka, Germany), the average for patients with atopic dermatitis 16.28 ± 8.36 g / m ² h, 24.25 for non-lesion A water content of ± 8.84 g / m ² h was shown.

However, the amount of water change after 1 week of use in the lesion was increased by 36.8% compared to before use of the product, and 7.5% more than in the case of non-lesion, and by 28.1% in the lesion after 2 weeks of use. The lesion showed an increase of 13.8%. This supports that the oxaspiro [2,5] octane-6-one of the present invention assists in improving skin barrier function along with the TEWL measurement results.

On the other hand, the skin is generally slightly acidic with a pH of <7, but the atopic patient is reported to have a pH value of up to 8% higher than that of the normal person. As can be seen in Figure 15 below, even in the case of this test using a skin pH meter (pH900PC, Courage & Khazaka, Germany) on average 5.06 ± 0.51 g / m ² h for patients with atopic dermatitis, 4.79 for non-lesion Skin acidity of ± 0.52 g / m ² h was shown. However, after 1 week of product use, the pH of lesions decreased by 1.9% and that of non-lesion decreased by 0.3%. After 2 weeks of product use, the pH of lesions decreased by 3.5% and that of non-lesion decreased by 1.2%. .

From the above description, those skilled in the art will appreciate that the present invention can be implemented in other specific forms without changing the technical spirit or essential features. In this regard, it should be understood that the examples and test examples described above are illustrative in all respects and not restrictive. The scope of the present invention should be construed that all changes or modifications derived from the meaning and scope of the appended claims and their equivalents, rather than the detailed description, are included in the scope of the present invention.

As described above, the compound 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1- according to the present invention Pharmaceutical compositions containing oxaspiro [2,5] octane-6-one as an active ingredient prevent skin changes, including atopic dermatitis, which is thought to be a complex combination of genetic, environmental, and immunological factors And a fairly good effect on treatment. Thus, the pharmaceutical composition of the present invention will be very high industrial applicability.

1 is 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1- of the present invention in atopic dermatitis animal model It is a graph which shows the pruritus inhibitory effect (a-e) by the concentration of oxaspiro [2,5] octane-6-one.

Figure 2 is a result of observation of infiltration of multinucleated leukocytes in the skin of an atopic dermatitis animal model, Figure 2a is a photograph showing the skin causing atopic dermatitis due to compound 48/80 injection, Figure 2b is a 4-hydroxy of the present invention -5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octan-6-one as said compound This is a photograph showing the infiltration inhibition effect of multinucleated leukocytes by 48/80 injection.

3 is a result of observation of infiltration of coral leukocytes in the skin of an atopic dermatitis animal model, FIG. 3a is a photograph showing the skin causing atopic dermatitis due to compound 48/80 injection, and FIG. 3b is a 4-hydroxy of the present invention. -5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane-6-one pretreated Photograph showing the case.

Figure 4 is a photograph of a large number of degranulated mast cells in the skin causing atopic dermatitis, Figure 4a is a photograph showing the skin induced atopic dermatitis due to compound 48/80 injection, Figure 4b is a 4- To hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octan-6-one It is a photograph showing the inhibitory effect of degranulation of mast cells due to the compound 48/80 injection.

Figure 5 shows 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2] on mast cells. , 5] Graph showing the effect of concentration of octane-6-one.

Figure 6 shows 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro for mast cell degranulation. 2,5] is a graph showing the effect of the concentration of octane-6-one.

FIG. 7 shows 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxa for histamine release from mast cells It is a graph showing the effect of the concentration of spiro [2,5] octane-6-one.

FIG. 8 shows 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxiranyl] -1- on calcium influx into mast cells. It is a graph showing the effect of concentration of oxaspiro [2,5] octane-6-one.

 Figure 9 shows 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro for cAMP in mast cells It is a graph showing the effect of concentration of [2,5] octane-6-one.

FIG. 10 shows 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2] for atopic symptoms , 5] The graph shows the results of measurement of the improvement of octane-6-one by visual evaluation by a dermatologist.

FIG. 11 shows 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2] for atopic symptoms , 5] Graph showing the results of measuring the degree of improvement of octane-6-one with SCORAD INDEX.

12 is a graph showing the effect of improving insomnia and pruritus by subjects with atopic dermatitis self-assessment.

It is a graph which measured the change of the water vaporization amount in the site of atopic dermatitis.

14 is a graph measuring the change in moisture retention in the skin of atopic dermatitis.

15 is a graph measuring the change in pH value in the skin of atopic dermatitis.

Claims (5)

4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2,5] octane as an active ingredient A pharmaceutical composition for treating atopic dermatitis, comprising -6-one. The compound according to claim 1, wherein the 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxalanyl] -1-oxaspiro [2 , 5] octane-6-one is a pharmaceutical composition for treating atopic dermatitis, characterized in that it contains 0.001 to 10% by weight based on the total weight of the composition. The method of claim 1, wherein the pharmaceutical composition is an ointment, cream, pastes, lotions, liniments, external liquids, tinctures, glycerogelatins, external acids, aerosols, Plaques, and oral capsules, tablets, pills, powders, granules; Cleaning agents for hair soaps, hair rinses, body cleansers and shampoos; Or creams, essences, body lotion cosmetics; pharmaceutical composition for treatment of atopic dermatitis, characterized in that the form. The pharmaceutical composition according to any one of claims 1 to 3, wherein said composition is in the form of a varnishing cream. The pharmaceutical composition according to any one of claims 1 to 3, wherein said composition is in the form of a shampoo.