WO2016190661A1

WO2016190661A1 - Cosmetic composition for inhibiting pruritus and alleviating atopic dermatitis, containing isosecotanapartholide as active ingredient

Info

Publication number: WO2016190661A1
Application number: PCT/KR2016/005534
Authority: WO
Inventors: 한창성; 김진국; 이강혁; 김건용; 박소연; 장준환; 윤지원
Original assignee: 에스케이바이오랜드 주식회사
Priority date: 2015-05-26
Filing date: 2016-05-25
Publication date: 2016-12-01
Also published as: KR20160139128A; CN107920974A; KR101831883B1

Abstract

The present invention relates to a cosmetic composition for inhibiting and relieving pruritus or alleviating atopic dermatitis, containing, as an active ingredient, isosecotanapartholide represented by chemical formula [1] below. According to the present invention, the cosmetic composition containing isosecotanapartholide is very safe since cytotoxicity has not been observed, is capable of inhibiting and relieving pruritus by inhibiting interleukin-31 (IL-31) or interleukin-33 (IL-33) among cytokines causing various types of pruritus, has an excellent ability of inhibiting a thymic stromal lymphopoietin (TSLP) cytokine, which is the top-level protein in abnormal signaling caused by an immune imbalance, which is the fundamental cause of atopic dermatitis, and has an excellent ability of inhibiting the expression of MDC and TARC chemokines in HaCaT cells, and thus the cosmetic composition can alleviate atopic skin.

Description

【Specification】

[Name of invention]

Cosmetic composition for suppressing itching and improving atopic dermatitis, containing isosecotanapasolide as an active ingredient

Technical Field

The present invention relates to a cosmetic composition for inhibiting itching and improving atopic dermatitis, and more particularly, to a composition for improving itching and improving atopic dermatitis, containing isosecotanapartholide (Isosecotanaparthol ide) as an active ingredient.

Background Art

Itching is a sensation caused by many skin diseases and is mainly associated with diseases such as atopic dermatitis, contact dermatitis, urticaria, nodular fever, um, chronic simple thyroid, insect bites, and eczema. This itch is caused by irritation of the skin nerve. When severely scratched or rubbed to remove the itch, hepatitis, cracks, ulcers, swelling, pigmentation, etc., and the skin becomes thicker if persisted. (Greaves et al, The Lancet., 348, pp. 938-40, 1996)

Clinically itching has two meanings, one that is irrelevant to itching, such as itching, such as hypersensitivity, sensation of pain caused by a needle piercing, with hypersensitivity to itching even with a very mild stimulus that did not cause itching. There is al lokness itch for one heterogeneous stimulus. The development of these two itching is caused by a variety of external factors (atopic dermatitis, contact dermatitis, urticaria, nodular yang, um, chronic simple mammary glands, nasal bleeding, mossy eczema). This leads to a vicious cycle that leads to an itching, which in turn leads to an itching and accompanying inflammatory disease. (Lee Gap Seok, Al lergy asthma respi r Di s2 (l): 8- 15, March 2014) Itching is intricately intertwined with inflammatory reactions in the skin, and blocking itching can be seen as a prior task in the treatment of various diseases caused by itching. Antihistamines, which are currently widely used as anti-itch medications, are not effective for atopic dermatitis. The reason is due to the fact that there is only one histamine in the various pathways that cause itching. (Budden) Ue J, Steinhof f M. Pathophysiology and therapy of pruritus in allergic and atopic diseases. Allergy 2010; 65: 805-821. Complex problem solving to reduce itching, inflammation and physical irritation can provide solutions to a variety of diseases that cause itching of the skin.

Cytokines play an important role in the intercellular interaction mechanisms, among which interleukin-3UIL-31 belongs to the interleukin-6 family, which is interleukin-31A and 0SMR (0ncostain M receptor). It consists of a heterologous Heterodimeric receptor complex. Interleukin-31 plays an important role in innate imunity and adaptive immunity in skin tissue in close proximity to the environment. Increased expression of interleukin-31 is associated with allergy or inflammatory bowel disease, as well as diseases including itching, such as atopic dermatitis. (C. Cornel issen et al. European Journal of Cell Biology 91 (2012) 552-566) Treatment with interleukin-31 may result in incomplete epidermal thickness, disruption of epidermal lipogenesis, and stratum granulosum differentiation of stratum basale. Induces weakening (Cornel issen, CJ Allergy Clin. Immunol. 2012, 129, 426-33.) Severe pruritus hair loss (Alopecia) and skin damage in experiments with interleukin-31 and overexpressing mice Turned out. (Di 1 Ion, SR Nat. Immunol. 2004, 5,752-760.) In particular, it plays an important role in diseases associated with itching, such as prurigo nodularis, chronic urticaria (cronic spontaneous urticaria) and allergic contact dermatitis. (Sonkoly, E. et al. J. Allergy Clin. Immunol. 2006, 117, 411-17., Raap, U. et al. Exp. Dermatol. 2010, 19, 464-66.) Interleukin-33GL-33) is present in cells of the skin surface. Severe scratches, pollen, ticks, etc. are stimulated to come out of the cell and combine with white blood cells, causing allergies. In patients with atopic dermatitis, interleukin-33 is known to be abundant. In recent experiments using mice that manipulated genes to make interleukin-33 about 10 times greater than wild-type, itching accompanied by itching on the face, legs, and tail of rats, leading to thickening of the skin. Symptoms of atopic dermatitis were shown. GM mice had about three times more mast cells that secrete histamine, which is the basis for itching. (Imai et al. PNAS, 2013, vol. 110, no. 34, 13921-13926)

Recent studies have shown that interleukin-31 and interleukin-33 are associated with skin inflammation and itching caused by dermatitis. Therefore, by investigating the effect of reducing the expression of interleukin-31 and interleukin-33 in human kerat inocytes, it is possible to search for foods, pharmaceuticals and cosmetic ingredients that are effective in relieving itching and treating dermatitis. It may be used to develop an itch treatment.

Accordingly, the present inventors have diligently researched to overcome the problems of the prior art, and in the case of cosmetic compositions for suppressing and alleviating itching containing natural compounds derived isosecotanaparthol ide, no cytotoxicity is found. Therefore, it was confirmed that it is possible to suppress and relieve itching by inhibiting IL-3K Inter leukin-31) or IL-33 (Inter leukin-33) among cytokines which are excellent in safety and cause various itching. To complete.

In addition, atopic dermatitis is a chronic and recurring inflammatory skin disease that can be easily diagnosed through the skin's swelling, eczema, itching, and inflammatory reactions. Is not yet clear. In the last two to three decades, atopic dermatitis has increased significantly compared to rural and developing countries, especially in westernized countries, supported by hygiene hypothesis (hygiene hypothesis). This hypothesis suggests that the growth of the immune system requires stimulation from the external environment, including bacteria, or other problems such as allergies due to problems with the immune system. Yazdanbakhsh, M., PG Kremsner, and R. van Ree, Allergy, Parasites, and the hypothesis Science, 296 (5567): 490-494, 2002].

Atopy is a complex immune response that affects certain sensitive genes, the environment, the extent of damage to the skin's outer walls, and immune factors. The main symptoms of atopy include swelling and eczema in the face of young children and eczema in the flexion of the joints in adults. Above all, the symptoms of itching are severe and cause serious problems in the social activities of patients. Dermatitis adds serious mental distress to a patient, as well as physical suffering from the disease.

Recent studies have shown that the immune imbalance that is the underlying cause of atopic dermatitis is the result of a variety of biological signal transductions and that the top level protein for these abnormal signaling is the thymic stromal lymphopoietin (TSLP) cytokine. When allergens infiltrate the body, TSLP-dong substances stimulate the dendritic cells to react, causing symptoms of atopic dermatitis. Specifically, in atopic dermatitis, when skin barrier is damaged by genetic and various environmental factors, it is easily exposed to various allergens penetrated from the outside, and keratinocytes secrete TSLP, a cytokine similar to IL-7. TSLP, also known as the 'master switch' of allergic inflammation, affects important cells that cause skin inflammation such as mast cells, basophils, and eosinophils, affects both innate and acquired immune responses, and induces Th2 immune reactions to induce atopic dermatitis. Ziegler SF, Art is D. Sensing the out si de world: TSLP regulates barrier immunity. Nat Immunol 2010; 11: 289 一 293. TSLP is increased in the skin and blood of atopic dermatitis patients. When allergens increase PAR-2 expression of keratinocytes, TSLP secretion in the epidermis increases, which causes Th2 inflammatory reactions to prevail, leading to clinical manifestations of atopic dermatitis. Lee EB, Kim KW, Hong JY, Jee HM, Sohn MH, Kim KE. Increased serum thymic stromal lymphopoietin in children with atopic dermatitis. Pediatr Allergy Immunol 2010; 21: e457- _e 460. On the one hand, mutations in the TSLP gene result in increased TSLP secretion and greater Th2 immune response [Wu WH, Park CO, Oh SH, Kim HJ, Kwon YS, Bae BG, Noh JY, Lee KH. Thymic stromal lymphopoiet in-act ivated invariant natural killer T eel Is trigger an innate allergic immune response in atopic dermatitis. J Allergy CI in Immunol 2010; 126: 290-299e4]. In addition, TSLP has been discussed as an important mediator for the progression of atopic dermatitis to asthma and allergic rhinitis in allergic march. TSLP is considered to be a target to prevent the development of atopic dermatitis and to prevent the progression to allergic march [ Zhang Z, Hener P, Frossard N, Kato S, Metzger D, Li M, Chambon P. Thymic stromal lymphopoiet in overproduced by kerat inocytes in mouse skin aggravates experimental asthma. Proc Nat 1 Acad Sci USA ^* 2009; 106: 1536-1541.

Meanwhile, there is a report that the serum concentration of chemokine (macrophage_derived chemokine), MDC ^ -TARC (thymus and ac tivat ionr egu 1 at ed chemokine), is significantly increased in patients with atopic dermatitis (Hijnen et. Al. , J. Allergy Clin.I 瞧 unol.113 (2) 334-340), MDC and TARC and serum concentrations of cyclosporin A or corticosteroids used as therapeutic agents for atopic dermatitis in patients with atopic dermatitis Has been reported (Y. Shimada et al., J. Dermatol. Sci., 34, 201-208, 2004), and MDC when INF—γ or TNF-α were treated in HaCaT cells in vitro. And TARC are expressed in a large amount, and it has been suggested that a substance capable of inhibiting such expression can be used as a therapeutic agent for atopic dermatitis (Horikawa et. Al., Int. Immunol., 14 (7) 767-773, 2002). Therefore, substances that inhibit the expression of chamoine, such as MDC or TARC can be used as an atopic dermatitis improving agent.

One of the main features of atopy is dryness caused by dysfunction and transepi dermal water loss (TEWL) of the skin barrier, mainly accompanied by swelling and inflammatory reactions. Therefore, regular skin softening lotion and the use of moisturizers are generally used in the treatment of atopy. Alternatively, glucocorticosteroids are known to be most effective in the treatment of early symptoms of atopic dermatitis. This method not only has anti-inflammatory effects, but also prevents colonization of S. aures (Staphylococcus aures) to prevent secondary infection. It also prevents atopic symptoms from getting worse. Topical steroids should be used for a short period of time to treat early eczema symptoms, and when used in combination with skin softening lotions, the effect is much better.

Pimecrolimus and tacrolimus are calcineurin inhibitors with immunomodulatory effects and are widely used as anti-inflammatory drugs. It is effectively used for sensitive areas such as the face because it lacks steroids, but the disadvantage is that you may feel temporary stinging.

In addition, because S. aures is proliferating in the skin of atopic patients, the superantigen secreted here further exacerbates the symptoms of atopy. Therefore, topical antimicrobial ointment prevents the growth of the bacteria and alleviates atopic symptoms. This method is more effective because it can prevent secondary infection when used with steroid products, but it is recommended to use an appropriate amount for a short period of time because it is resistant to long term use. In addition, cyclosporin ACcyclosporin A), which blocks calcineurin dependent pathways, is used for oral administration by reducing the expression of proinflammatory cytokine such as IL-2 and IFN-gamma. This method is only suitable for patients with severe incurable diseases because it can be toxic to the kidneys despite its effective ability to cure atopy.

In addition, existing atopic dermatitis treatments have been used to suppress calcineurin and reduce the cytokine expression, such as cyclosporin and FK506. The steroid-based external treatments that reduce resistance and relieve skin itching and pruritus also have problems such as reduced immunity and growth inhibition when children are used for a long time.

Azathioprine is a representative immunosuppressor effective for skin diseases by affecting purine nucleotide synthesis and metabolism. Alternatively, with antihistamines, corticosteroids There is a very effective phototherapy when used. This is a method that exposes UVB wavelength of 280-320 陋 and UVA wavelength of 340-400nm to the whole body, and it is reported that it is very effective for adults, but young children can use it only after puberty because the skin is still weak.

As such, the current treatments are those for which there is a lot of side effects. Therefore, there is a need for development of a medicinal herb with excellent efficacy without such side effects.

Currently, many domestic school and bio company researchers have been researching and commercializing improvement agents for improving atopic dermatitis, and most of the products developed are disappearing at the early stage of market entry. This is because hypoallergenic cosmetics are being developed as atopic dermatitis improvement products to enhance the moisturizing effect of the skin vaguely rather than to develop products that have a pathological mechanism that causes and worsens atopic dermatitis.

In view of the above, the present inventors have endeavored to develop an excellent substance capable of improving atopic skin without side effects and skin irritation. As a result, the present inventors have found that natural product-derived compound isosecotanapartholide (Isosecotanaparthol ide) In the case of cosmetic composition, no cytotoxicity was found, and the safety was excellent, TSLP thymi c stromal lymphopoiet in), the highest protein of abnormal signaling caused by immune imbalance which is the root cause of atopic dermatitis, was excellent in cytokine inhibition and MDC in HaCaT cells. And it was confirmed that the atopic skin can be improved overall by inhibiting the expression of chamokine of TARC and completed the present invention.

[Detailed Description of the Invention]

[Technical problem]

Therefore, the main object of the present invention is to suppress the itching and relieve itching by inhibiting IL-3K Inter leukin-31) or IL-33 (Inter leukin-33) among the cytokines that cause various itching It is to provide a cosmetic composition for suppressing and alleviating itching containing napa solide as an active ingredient. In addition, another object of the present invention is a cytotoxic, non-cytotoxic top-level protein of abnormal signaling caused by immune imbalance that is a fundamental cause of atopic dermatitis

The present invention provides a cosmetic composition for improving atopic dermatitis, which is excellent in TSLP cytokine inhibitory activity and excellent in inhibiting the expression of MDA and TARC by chamoine expression as an active ingredient.

Technical Solution

According to one aspect of the invention, the present invention provides a cosmetic composition for inhibiting and alleviating itching, containing isosecotanaparthol ide represented by the following formula [1] as an active ingredient.

Chemical formula [1]

According to one aspect of the present invention, the present invention provides a cosmetic composition for improving atopic dermatitis, containing isosecotanapartholide (Isosecotanaparthol ide) represented by the following formula [1] as an active ingredient.

Chemical formula [1]

The compound "isocecotanapasolide" identified in the present invention is various It is contained in natural products. For example, it is contained in the heather (Artemisi a iwayomogi), the leaflets (Artemi sia princeps var. Oriental is 'Pampan' Hara), or the side. The isosecotanapasolide compound has been disclosed as a novel whitening agent, whitening cosmetic composition [JP 5307369]. However, there is no study on the inhibition and alleviation of the itch or improvement of atopic dermatitis of the compound "isoceconata pasolide" identified in the present invention.

Accordingly, the inventors of the present invention have confirmed that isosecotanapasolide identified from the leaf lobe is not only effective in suppressing and alleviating itching, but also in improving atopic dermatitis, thereby completing the present invention. The term 'itch itch' in the present invention is also referred to as pruritus, which means that it is caused by various dermatitis.

In the present invention, the isosecotanapaholide (Isosecotanaparthol ide) may be contained from 0.00001 to 5% by weight relative to the total weight of the cosmetic composition, preferably 0.0001 to 0.5% by weight is contained, characterized in that not limited to Do not. If isosecotanapasolide is contained in less than 0.0001% by weight, the effect of itching and atopic dermatitis due to the active ingredient is too small when added to cosmetics, and when it exceeds 0.5% by weight, there is no problem in skin safety or effect. Since the isosecotanapa solide is purified from natural products, it is difficult to obtain in large quantities, which is undesirable from an economic point of view.

In the present invention, the isosecotanapartholide (Isosecotanaparthol ide) may be prepared by a chemical synthesis method known in the art or may be separated from natural products, preferably from a leaf (Artemi sia princeps var. Or iental is) It is characterized by being separated.

As an example of a preferred method of extracting the leaflets, the leaflets were extracted at room temperature or 60 ^° C using a concentration of 0 to 95¾ ethanol and extracted for 3 days or more, and then the filtrate obtained by filtration was concentrated to remove the solvent to obtain an extract. Nucleic acid after dispersing about 2 to 20 times its weight, preferably about 2 to 5 times the volume of water. Chloroform, methylene chloride, ethyl acetate, glycerin or propylene glycol, preferably nucleic acid, chloroform or ethyl acetate, more preferably ethyl acetate is added 1 to 5 times by adding about 0.1 to 0.5 times the volume of water, preferably 2 to 5 times. Fractionation four times yields the bile nonpolar solvent soluble extract of the present invention.

The non-polar solvent soluble extract of the leaflets obtained by the above-mentioned method was dissolved in an alcohol having 1 to 4 carbon atoms, preferably in methanol and adsorbed onto a C18 column, followed by a nonpolar solvent, preferably dichloromethane: methane. The mixture was mixed to obtain the fractions, adsorbed onto silica gel, followed by silica gel column chromatography 2 to 5 times to separate the active fractions, and finally, the isosecotanapasolide of the present invention was obtained using high performance liquid chromatography. can do.

The present inventors paid attention to isosecotanapasolide, which is a component that inhibits the expression of interleukin-31 and interleukin-33 in skin cells, after thin-film chromatography of the leaf extracts and separation of each component. The isosecotanapasolide is a single compound that is purified from wormwood or asteraceae, and there is no example used to relieve itching, and for the first time in the present invention, the isosecotanapasolide as a composition for suppressing itching in itching It is found that it can be used.

In the present invention, the cause or form causing the itch is not particularly limited, but preferably, inflammatory dermatitis, atopic dermatitis, dermatitis due to roughness of skin, sweat band, erosion, frostbite, contact dermatitis, seborrheic dermatitis, psoriasis Or is caused by the psoriasis. In the case of the itch, the continuous itch causes the skin to be constantly rubbed, scratched or pinched. As a result, secondary skin damage such as skin rash, abrasion, thymus, positivity, hyperpigmentation or reduction of pigmentation is induced, and various substances inducing inflammatory reaction in the skin are secreted, and this secretion is itchy again. This increases the circulation of itching-scratching.

In the present invention, the isosecotanapa solide (I sosecotanapar t ho Π de) is IL-31 (Int er 1 euki n-31) or It is characterized by exhibiting an itching suppression and alleviation effect by reducing the release amount of cytokines such as IL-33 (Inter leukin-33).

According to the experimental example of the present invention, the isosecotanapasolide of the present invention is excellent in inhibiting the expression of IL-31 and IL-33 associated with itching in human keratinocytes (HaCaT cel l). Confirmed. From these results, it can be seen that isosecotanapasolide of the present invention can suppress and relieve itching by inhibiting the expression of the cytokines IL-31 and IL-33 released when itching occurs. (See Experimental Examples 2 to 4).

In addition, the isosecotanapasolide of the present invention inhibits the expression of IL-1beta (IL-Ιβ) and interleukin-6 (IL-6) induced by TNF-alpha and IFN-gamma and is associated with immune hypersensitivity reactions. It was confirmed that the inhibition of the expression of interleukin-6 and interleukin-1beta can be significantly reduced, and it was confirmed that isosecotanapasolide exhibited a very good anti-itch effect (see Experimental Example 2).

In addition, the cytotoxicity of isosecotanapasolide was confirmed in the keratinocytes of the skin, and no cytotoxicity was found, indicating that the safety was excellent (Experimental Example 1).

In the present invention, the isosecotanapaholide (Isosecotanaparthol ide) is characterized in that it has an atopic dermatitis improvement effect by thymi c stromal lymphopoi et in (TSLP) inhibitory ability.

According to the experimental example of the present invention, in the case of isosecotanapa solide of the present invention, it was confirmed that TSLP inhibitory ability which is a fundamental cause of atopic dermatitis in human keratinocytes (HaCaT cel l) was excellent. From these results, it can be seen that the isosecotanapasolide of the present invention can exhibit an atopic dermatitis improvement effect by inhibiting TSLP (see Experimental Example 5 and Table 5).

. In the present invention, the isosecota 8 nafa solide (Isosecota 卿 arthol ide) is characterized in that it has an atopic dermatitis improvement effect by inhibiting the expression of macrophage-derived chemokine (MDC). In the present invention, the isosecotanapartholide (Isosecotanaparthol ide) is characterized in that it has an atopic dermatitis improvement effect by inhibiting the expression of thymus and act ivat ionregulated chemokine (TARC).

According to the experimental example of the present invention, in the case of isosecotanapa solide of the present invention, it was confirmed that the effect of inhibiting the concentration of chemokines MDC and TARC in the serum of atopic dermatitis patients. From these results, it can be seen that the isosecotanapasolide of the present invention can exhibit an atopic dermatitis improvement effect by inhibiting chemokine MDC and TARC (see Experimental Example 6, FIGS. 12 and 13). In the present invention, the cosmetic composition is supple cosmetics, nourishing cosmetics, essence, nutrition lotion, nutrition cream, eye cream, massage cream, cleansing cream, cleansing products, cleansing water, powder, pack, hair cosmetics, body lotion, body At least one formulation selected from the group consisting of creams, body oils, body essences or body cleansers. The hair cosmetics include hair tonic, hair conditioner, hair lotion, shampoo, hair rinse, treatment, hair cream, hair oil, hair dryer, hair preservative, hair colorant, hair wave agent, hair bleach, hair gel, hair Glazes, hairdressers, hair lacquers, hair moisturizers, hair mousses and hairsprays, but is not limited thereto.

When the present invention is used as a cosmetic composition, in addition to isosecotanapasolide as an active ingredient, it may include components commonly used in cosmetic compositions, such as water-soluble vitamins, oil-soluble vitamins, polymer peptides, polymer polysaccharides, sphingos. Lipid and seaweed extracts and the like. In addition, as a compounding component which may be added to a cosmetic composition, it is an oil-fat component and a moisturizer _. , Emollients, surfactants, organic and inorganic pigments, organic powders, UV absorbers, preservatives, fungicides, antioxidants, plant extracts, pH adjusters, alcohols, pigments, flavorings, blood stimulants, antiseptics, restrictions First, purified water and the like can be mentioned.

In addition, when the composition of the present invention is used as a pharmaceutical composition, isosecotanapasolide as an active ingredient may be used depending on the use, formulation, and formulation purpose, so long as it can exhibit an itch inhibiting effect or an atopic dermatitis improving activity. It can be included in an amount (effective amount). Preferably, the pharmaceutical composition of the present invention may contain isosecotanapasoleide in an amount of 0.0001 to 0.5% by weight based on the total weight of the composition.

When the composition of the present invention is used as a pharmaceutical composition, it may further include suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.

When the composition of the present invention is used as a pharmaceutical composition, the preferred dosage of the pharmaceutical composition depends on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art. have. However, for the desired effect, the pharmaceutical composition of the present invention is preferably administered at 0.0001 to 100 mg / kg, preferably 0.001 to 10 mg / kg per day. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.

When the composition of the present invention is used as a pharmaceutical composition, it can be administered orally or parenterally, and is preferably applied by parenteral administration, more preferably by topical application (topi cal appl i cat ion).

The pharmaceutical composition of the present invention can be prepared in any formulation that can be applied to the skin, such as liquid, cream, paste, solid, etc., cream, lotion, liquid essence type to improve itching or atopic dermatitis by adding conventional additives And aerosol types of these formulations.

Advantageous Effects

As described above, the isosecotanapasolide of the present invention can be safely used in cosmetic compositions because it has no cytotoxicity and skin side effects, and at the same time inhibits the expression of interleukin-31 and interleukin-33 receptor in keratinocytes and at the same time TNF- It inhibits the expression of interleukin-1 beta and interleukin-6 caused by alpha and IFN-gamma, thereby showing an excellent effect on suppressing and alleviating itching. In addition, isosecotanapasolide of the present invention is TSLP thymi c stromal lymphopoiet in the top protein of abnormal signaling caused by immune imbalance which is a fundamental cause of atopic dermatitis The cytokine inhibitory ability is excellent and the ability to inhibit the expression of chamokine expression of MDC and TARC in HaCaT cells, it is possible to improve atopic skin.

【Brief Description of Drawings】

Figure 1 shows the analysis of high performance liquid chromatography of the leaf extract.

Figure 2 shows the analysis of high performance liquid chromatography of isosecotanapasolide 0.05% solution.

3 is a diagram showing the results of confirming the cytotoxicity of isosecotanapasolide.

Figure 4 is a view showing the results confirming the IL-lbeta secretion control of isosecotanapa solide.

5 is a view showing the results of confirming the regulation of IL-6 secretion of isosecotanapasolide.

6 is a diagram showing the results of confirming the regulation of IL-33 secretion of isosecotanapasolide.

7 is a diagram showing the results of confirming the regulation of IL-31 secretion of isosecotanapasolide.

8 is a diagram showing the results of confirming the IL-31 and IL-33 inhibitory effects of isosecotanapasolide at the gene level.

9 is a diagram showing the results of confirming the IL-31 and IL-33 inhibitory effects of isosecotanapasolide at the protein level.

10 is a view showing the results of evaluating the itching effect of isose.Cotanapasolide through clinical trials.

Fig. 11 shows the results for TSLP inhibitory activity of isosecotanapasolide.

12 is a graph showing the results of TARC inhibitory ability of isosecotanapasolide.

Figure 13 shows the results for the MDC-1 inhibitory ability of isosecotanapasolide Drawing.

14 is a view showing the results for the atopic skin improvement effect of the present invention formulation example 3 and comparative formulation example 3.

[Form for implementation of invention]

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only intended to illustrate the invention, and the scope of the invention is not to be construed as limited by these examples. Example 1 Preparation of Isececotanapasolide

The compound isosecotanapasolide was isolated from Artemisia princeps as follows.

First, dry the young leaves purchased at Gyeongdong Market, and add 50 L of 95¾ ethanol to 5 kg of shredded outpost, and extract it three times or more at room temperature for 3 days. The filtrate was filtered using a vacuum condenser (EYELA, N-1000, Japan). Concentration under reduced pressure produces a crude extract. 200 g of the crude extract was suspended in 2L distilled water, and then the same amount of ethyl acetate was added and extracted six times. The mixture was extracted with a separatory funnel, and the ethyl acetate layer was recovered. The ethyl acetate layer was concentrated under reduced pressure, and 70 g of ethyl acetate soluble extract was extracted. Obtained.

The ethyl acetate soluble extract of the above-obtained lobe was dissolved in methanol solution, and then fractions were deposited on silica gel (Merck, Merck, trade name: 9385) layered on a column (4.5x40 cm) using a mixed solution of dichloromethane: methanol = 80: 1. Was adsorbed, and silica gel column chromatography was carried out under the conditions of dichloromethane: methanol (80: 1 → 50: 1 → 30: 1 → 20: 1 → 15: 1 → 5: 1 → 1: 1) to increase the eluate. Divided into 6 fractions and obtained in the third elution using high performance liquid chromatography under the conditions described in Table 1 to obtain isosecotanapa solide having the following physical properties, which was used in the following experimental example. High performance liquid chromatography analysis chart of the petiole extract under the conditions described in Table 2 is shown in FIG. Indicated.

[Table 1]

The NMR instrument analyzed the structure of the compound separated by Varian (Garian, GEMINI, 400 MHz) and C ¹³ -NMR, and VMS (Aldrich) solvent. It was confirmed that the NMR results are consistent with the published data. [Hanna Ahn. et al. , Arch Pharm Res Vol 26, No 4, 301-305, 2003]

¾-NMR (DMSO- d ₆ , 400 MHz): δ 1.70 (1H, m H-8) 1 · 85 (1H m H-8 ') 2.05 (3H, s H-14), 2.08 (lH, d, H -2), 2.11 (3H, s , H-15), 2.45 (2H, m, H- 9), 2.66 (lH) dd, J = 18.2,6.2Hz) H-2 '), 3.05 (lH, m ₍ H-7), 4.55 (lH, s, H-6), 5.02 (lH, d, J = 5.6Hz, H-3), 5.61 (lH, brs, -0H), 5.73 (lH, d, J = 2.5Hz, H-13), 6.11 (lH, d, J = 2.9Hz, H-13 ')

^, C-NMR (DMS0-i¾, 100MHz): 613.4 (C-15) ₎ 26.8 (C-8), 29.7 (C-14), 39.1 (C- 9), 41.3 (C-7), 44.3 (C-2), 69.7 (C-3), 75.4 (C-6), 121.6 (C-13), 135.7 (C-5), 139.1 (C 11), 169.6 C-12), 175.0 (04), 203.4 C-1), 207.6 (010) Reference Example 1: Purity Analysis of Isececotanapasolide

Purity analysis was performed using high performance liquid chromatography (HPLC) under the conditions described in Table 2 to determine the purity of the isosecotanapasolide obtained in Example 1, and the results are shown in Table 3 below. .

Table 3

As a result of the analysis, as shown in Table 3, it was found that the purified product of Example 1 was purified to a content of 99.9% of the area of the high performance liquid chromatography. Example 2 Preparation of Purified Isosecotanapasolide 0.05% Solution

Whatman # 5 filter paper after completely dissolving in a mixture of purified water and butylene glycol mixture (30 weight ¾) for 1 hour at room temperature to contain 0.05% by weight of the compound isosecotanapasolide obtained in Example 1 Filtration was performed to prepare a 0.05% by weight solution of isosecotanapasolide. In addition, the analysis results of high performance liquid chromatography (HPLC) of isosecotanapasolide 0.0 solution are shown in FIG. 2. Experimental Example 1 Measurement of Cytotoxicity in Human Skin Cell Line HaCaT Cells

In order to evaluate the cytotoxicity of isosecotanapasolide isolated in Example 1, CCK-8 assay was performed using a constituent cell line of human skin, a stratum corneocyte HaCaT cell line (CLC Celll ine serve ice, Germany). It was. The cell viability was measured by CCK-8 ki t. Cel l on a 96 wel l plate 2.5 χ 10 ^{4 χ} 90 / ^ per wel l After dispensing into media, the cells were incubated for 24 hours in a 37 ⁰ C C0 ₂ incubator. Thereafter, isocetacoanapasolide (1.25, 2.5, 5, 10 ng / mL) was applied to HaCaT cells by concentration, and applied for 24 hours, followed by kit sol'n lO, shaded, and placed in a 37 ° C incubator 1 After time the absorbance was measured at 450 ran. The results are shown in FIG. As shown in Figure 3, it was confirmed that no cytotoxicity at all concentrations treated with isosecotanapasolide of the present invention. Experimental Example 2: Confirmation of cytokine secretion regulation (ELISA)

ELISA analysis was performed to confirm the regulation of cytokine secretion against isosecotanapasolide isolated in Example 1. HaCaT keratinocytes used in the experiment were dispensed with 2xl0 ⁵ cells / mi in a 60 匪 dish and attached at 37 ° C, 5% C0 ₂ incubator for 24 hours. After treatment with isosecotanapasolide of the present invention for 1 hour by concentration and IFN_Y (10 ng / mL) and TNF-cx (10 ng / mL), the supernatant of cells was collected after 24 hours. It was used for the experiment. The cytokines of IL-lbeta, IL-6, IL-31, and IL-33 were measured using an ELISA kit sold by eBioscience (CA, USA). In more detail, 100 / ^ of capture Ab diluted with coating buffer was added per well and overnight at 4 ⁰ C. lx assay diluent per well

After putting 200 units at room temperature for 1 hour, the standard and sample distilled from the highest concentration were added 100 ^ per well and reacted at room temperature for 2 hours. Subsequently, detection Abs diluted with lx assay diluent were added per well and reacted at room temperature for 1 hour, followed by avidin-HRP distilled with lxassay diluent per well for 30 minutes at room temperature. Finally, the substrate solution was added to 100 / ^ per well and allowed to stand at room temperature for 15 minutes, the stop solution was added to 50 / ^ per well to stop reaction and absorbance was measured at 450 ran. The results are shown in Figures 4-7. As shown in Figures 4 to 7, it was confirmed that isosecotanapasolide in the HaCaT keratinocyte cell culture medium reduced the amount of IL-31, IL-33 released in a concentration-dependent manner. Experimental Example 3: Reverse transcript ion-PCR analysis Reverse-transcription polymerase chain reaction (RT-PCR) was performed with the isosecotanapasolide separated in Example 1 as a sample and cytosed at the gene level. The degree of inhibition of release of caine was measured. In more detail, the separation of total NA was performed using the RNeasy Plus mini kit (Qiagen, Valencia, CA) and purified using the manufacturer's protocol. The first strand of cDNA treated with DNase was used. This reaction was performed using arbitrary primers and M-MLV reverse transcriptase (Invitrogen Corp., CA, USA). The general PCR conditions ： 30 35 cycles at 94 ° C for 2 10 min, 94 ° C for 30 s 3 min, 50 ° C-58 ° C for 30 s 1 min, 72 ° C for 30 s 1 min, and 72 It was carried out at ° C for 4 7 min conditions. Image is

Analysis was carried out using Quantity One software (Bio-Rad, CA, USA). Primers used are shown in Table 4 below.

Table 4

In the case of IL-31, IFN-γ was reacted to HaCaT cells at a concentration of 20 ng / mL for 24 hours, and IL-33 was used for TNF-a (20 ng / mL) and IFN-γ (20 ng / mL) to HaCaT cells. mL)) and reacted for 24 hours. The results are shown in FIG. As shown in Figure 8, as a result of confirming the reduced ability of IL-31, IL-33 to isosecotanapa solide was confirmed that the reduced expression of IL-31, IL-33. Experimental Example 4: Protein blot analysis

In this Experimental Example, to determine the degree of inhibition of cytokine release at the protein level using isosecotanapasolide isolated in Example 1 as a sample. Western blot analysis was performed. More specifically, hDPCs are dissolved in RIPA buffer containing 50 mM Tris, pH 8.0, 150 mM NaCl, .1% NP-40, 0.1% SDS, 0.5% deoxycholic acid, ImM PMSF Mix protease inhibitor (Roche Applied Science, Indianapolis, IN) for 15 minutes on ice at 4 ° C

Centrifugation was performed at 20,000 xg for 10 minutes. The supernatant was re-centrifuged for 10 minutes and protein concentration was measured using a BCA protein assay kit (Bio-Rad, Hercules, CA, USA). Protein (20 // g) was isolated by polyacryl amide gel electrophoresis (SDS-PAGE) and adsorbed onto polyvinyl idene fluoride (PVDF) membrane (Millipore Corp, Bedford, Mass.). The membrane was reacted in PBS containing 0.1¾ Tween-20 and 5% skim milk (non-fat milk) for 2 hours at room temperature, and the primary antibody IL-31 diluted with PBS / 0.2% BSA for 1 hour. And probed using IL-33. After washing, the membrane was reacted with an anti-rabbit with secondary HRP or an anti-mouse antibody with ARP (Amersham, Arlington Heights, IL) and the band Visualization was performed with the ECL Advance kit (Amersham). Normalized to a loading control (Act in) band. In order to confirm the regulation of protein levels of the cytokines IL-31 and IL-33 associated with itching, the concentration of IFN-γ in HaCaT cells at a concentration of 20 ng / mL was observed for IL-31.

Reaction was performed for 24 hours, and IL-33 was reacted with HaCaT cells at the concentration of TNF-a (20 ng / mL) and IFN-γ (20 ng / mL) for 24 hours. The results are shown in FIG. As shown in FIG. 9, it was confirmed that isosecotanapasolide reduced the expression of IL-31 and IL-33 at the protein level in a concentration-dependent manner. Experimental Example 5: TSLP of isosecotanapasolide using real-time PCR

Inhibition test

5-1. Total RNA Isolation and cDNA Synthesis

The cDNA to be used for real-time PCR was synthesized by extracting total RNA after 24 hours of treatment of the compound isosecotanapasolide lysate of Example 2 with HaCaT cell line. Specifically, TrizoKlnvitrogen, Carlsbad, Total RNA was extracted using li). In order to perform cDNA synthesis using Total RNA, the total reaction solution 20 // «was composed of the following compositions. 5X PrimeScript Buffer (Kit code RR037A, Lot A1201-1) with PrimeScript RT Enzyme Mix (Kit code RR037A, Lot A1201-1) 1 with Oligo dT Primer (50 ^ M) (Kit code RR037A, Lot A1201-1) with Random 6mers (100 ^ M) (Kit code RR037A, Lot A1201-1) 4 ^ were mixed and placed in a tube and stored on ice. Total RNA was added to the tube to make the total reaction solution 20 ^. Then, the mixture was mixed three times with mild vortexing and stored on ice. This using a PCR machine

After reacting at 37 ⁰ C for 15 minutes, reaction was performed at 85 ° C for 5 seconds and treated with 4 ° C. The finished cDNA was used for real-time PCR analysis in the following manner.

5-2. TSLP low resolution test

TSLP (thymic stromal lymphopoiet in) is classified as a top cytokine that initiates type 2 helper T cell mediated immune deflection, which is thought to be the cause of atopic dermatitis.

In order to confirm the reduction effect of 0.05% DMS0 lysate of the compound isosecotanapasolide of Example 1 on TSLPCthymic stromal lymphopoietin expression of human keratinocytes HaCaT, the cDNA real-time PCR was used. Taqman method was run.

As a comparative substance, quercetin (sigma), naringin (sigma), and hesperidin (sigma), which are well-known compounds for anti-inflammatory effect, were dissolved in DMS0 at the same concentration, and then TSLP cytokines were changed. The experiment was performed using Taqman Primer & Pi) be (HS00263639, AB Applied Biosystems, USA) and Taqman Gene Expression Master Mix specific to the TSLP in cLNA template 1 ^ of ljug / z ^ concentration. Final reaction samples were prepared and measured using an Applied Biosystems ABI 7500 Real-time PCR system (AB Applied Biosystems, USA).

In more detail, a semi-aqueous solution for the analysis of GAPDH and TSLPCthymic stromal lymphopoietin was performed to perform real-time PCR. The reaction liquid for GAPDH analysis was GAPDH (Hs99999905, Lot 682967) 1 ^ and. DW 5 ^ and Master Mix (2X) (TaqMan Gene Expression Master Mix L / N 0810037, P / N 4369016) and cDNA were made by mixing well. The reaction solution for the analysis of TSLPCthymic stromal lymphopoietin was made by well mixing TSLP (Hs00263639) 1 ^ and DW 5 / ^ and Master Mix (2X) (TaqMan Gene Expression Master Mix L / N 0810037, P / N 4369016) with cDNA. . The prepared reaction solution was placed in a real-time PCR reaction plate (optical 96-well Reaction Plate with Barcode, part No.4306737). To the same plate, add each of the cDNA diluted X10 and X100 with HaCaT cDNA 2 // «and Easy Dilution (Kit code RR037A, Lot A1201-1) to prepare the standard curve. The cDNA prepared above was added to the reaction solution and reacted with real-time PCR Cycles.

Real-time PCR reactions were first repeated samples at 94 ⁰ C, 10 minutes for initial denaturation and then amplified a total of 60 cycles. The time and temperature for each cycle consisted of 10 seconds at 94 ⁰ C, 10 seconds at 60 ° C., and 30 seconds at 25 ° C. Expression of the target gene

Comparisons were made with relative values through calibration quantification of the internal control gene GAPDH (Glyceraldehyde 3-phosphate dehydrogenase) by the threshold cycle method. As a result, the following Table 5 and the result to, untreated and non ^"in the control group in Example 1, the compound isopropyl three cotta Napa sole fluoride 0.05% solution was reduced significantly to TSLP at least 60% of, as shown in Figure 11 It was confirmed that significantly reduced compared to other compounds.

[Table 5]

Experimental Example 6: TARC, MDC-1 chemokine inhibition experiment HaCaT keratinocytes were aliquoted into 2 ^× 10 ⁵ cells / mL in a 60 讓 dish and attached for 24 hours in a 37 ⁰ C, 5% C0 ₂ incubator. The supernatant of the cells was pretreated with isosecotanapasolide dissolved in DMS0 for 1 hour and treated with IFN-y (10ng / mL) and TNF-a (10ng / mL) for 24 hours. Was collected and used for the experiment. Chemokine of TAR (：， MDC-1 was measured using an ELISA it sold by eBioscience (CA, USA). Briefly, the capture Ab diluted in coating buffer was added at 100 | jL per well at 4 ° C. l Add 200 // ί of assay diluent per well and leave at room temperature for 1 hour, then add the standard and sample diluted from the highest concentration to 100 ^ per well and react at room temperature for 2 hours. per well of detection Ab diluted with lxassay diluent

After 100 / ^ reaction and reaction at room temperature for 1 hour, avidin-HRP diluted with lxassay diluent was added at 100 ^ per well and reacted for 30 minutes at the lab. Finally, the substrate solution was added 100 ^ per well and allowed to stand at room temperature for 15 minutes. Then, the stop solution was added 50 / ^ per well to stop the reaction and absorbance was measured at 450ran. As a result, chemokines of TARC and MDC-1, as shown in Figs. 12 and 13, are 1.25, 2.5, 5,

It can be seen that the concentration-dependent decrease with the concentration, the effect of improving atopic dermatitis was excellent.

Formulation Example 1 Preparation of Nutritional Lotion

Nutritional lotion in the cosmetic solution containing a solution of Example 2 was prepared in the composition shown in Table 6.

[Table 6]

No. Raw Material Formulation Example 1 Comparative Formulation Example 1

Example 2 2.0-

2 sitosterol 1.70 1.70 3 Polyglyceryl 2-Late 1.50 1.50

4 Ceramides 0.7 0.7

5 Ceteares -4 1.2 1.2

6 cholesterol 1.5 to 1.5

7 Dicetylphosphate 0.4 0.4

8 concentrated glycerin 5.0 5.0

9 Sunflower oil 10.0 10.0

10 Carboxyvinyl Polymer 0.2 0.2

11 Xanthan Gum 0.3 0.3

12 trace amounts of preservatives

13 flavor traces trace amount

14 Residual water remaining

Formulation Example 2 Preparation of Nutrition Cream

Cosmetic cream containing the solution of Example 2 was prepared in the composition shown in Table 7.

[Table 7]

No. Raw Material Formulation Example 2 Comparative Formulation Example 2

Example 2 2.0-

2 sitostere 4.0 4.0

3 Polyglyceryl 2-Olate 3.0 3.0

4 Ceramides 0.7 0.7

5 Ceteares -4 2.0 2.0

6 Cholesterol 3.0 3.0

7 Dicetylphosphate 0.4 0.4

8 concentrated glycerin 5.0 5.0

9 Sunflower oil 22.0 22.0

10 Carboxyvinyl Polymer 0.5 0.5

11 Triethanolamine 0.5 0.5

12 trace amounts of preservatives 13 flavor traces trace amount

14 Residual water remaining

Total 100 100

Formulation Example 3: Preparation of Massage Cream

A massage cream in the cosmetic composition containing the solution of Example 2 was prepared in the composition of Table 8 below.

[Table 8]

Formulation Example 4 Preparation of Haat Tonic

Hair tonic in the cosmetic solution containing the solution of Example 2 was prepared in the composition of Table 9 below. [Table 9]

Formulation Example 5 Preparation of Air Conditioner

Hair tonic in the cosmetic solution containing the solution of Example 2

Prepared by the composition.

Table 10

No. Raw Material Formulation Example 5 Comparative Formulation Example 5

Example 2 2.0-

2 cetane 3.5 3.5

3 Self-emulsifying glycerin monostearate 1.5 1.5

4 Propylene Glycol 2.5 2.5

5 Stearylarytylbenzyl Ammonium Chloride (25%) 7.0 7.0

6 Methyl Paraoxybenzoate 0.3 0.3

7 pigment appropriate amount

8 flavor appropriate amount 9 Residual water remaining

Total 100 100 Experimental Example 7: Evaluation of Clinical Effect Experiment (Improved Itching)

The cosmetics of Formulation Example 2 and Comparative Formulation Example 2 were used to evaluate the improvement of itching. Forty patients who had severe skin itch due to atopic dermatitis, eczema, urticaria, and sea layer, no other systemic diseases, and no oral antibiotics and immunosuppressants in recent months were selected. The cause of the itch was not distinguished, and only the degree of feeling of itching was selected based on the intensity of the initial five or more. The ages ranged from 20 to 45 years. The average age was 31.5 years old. There were 23 men and 17 women. Patients did not use topical steroids within a week prior to the start of the study and restricted the use of topical steroids during the study. The degree of itching (pruritus) after 30 minutes and 1 hour after the application of the sample prepared by Comparative Example 2 to the site defined as the affected part of the nutrition cream prepared according to Formulation Example 2 and Comparative Example 2 of Formulation Example 2 Was quantified according to subjective judgment, and then the sample prepared by Formulation Example 2 was applied to the same site once to quantify the degree of itching (pruritus) for 30 hours at three-minute intervals according to subjective judgment. The itch relief assessment divided the intensity of the itch by a number between 1 and 10 to indicate the intensity of the itch that is currently felt. The average value (% itch activity) obtained by dividing the intensity value obtained with each time by dividing the initial intensity value by a percentage is shown in Table 11 below with time. In addition, the results are shown in FIG.

Table 111

Time (min) Itching Active (¾) Standard Deviation Comparative Example Before Treatment 0 100.0 0.0 Comparative Example Treatment After 30 Minutes 30 91.5 12.4 Comparative Example Treatment After 60 Minutes 60 85.0 13.9

Before Preparation

Preparation Example 30 minutes passed 90 36.2 24.9 60 minutes of preparation process 120 7.3 12.4 90 days of preparation process 150 1.3 4.8 120 minutes of preparation process 180 0.9 4.1 _.

Preparation 150 minutes after treatment 210 ^' 1.8 5.4 Preparation Example after 180 minutes 240 2.2 5.9 Experimental results, as shown in Fig. 10, 91.5% after 30 minutes after the initial itch strength after applying Comparative Formula 2 to the lesion site, After 60 minutes, it was lowered to 85.0%, but when Formulation Example 2 containing Example 2 was applied to the same lesion, the itch intensity rapidly decreased to 36.2¾ after 60 minutes, to 7.3% after 60 minutes, and after 90 minutes. After and after that it almost decreased to the level of itching. Therefore, it was confirmed that Example 2 contained in Formulation Example 2 in the present invention has a marked effect in relieving or suppressing itching. Experimental Example 8: Atopic dermatitis improvement effect investigation

Clinical evaluation of the atopic skin improvement effect on the cosmetic formulation of Formulation Example 3 was measured. Formulation Example 3 In order to evaluate the effect of improving the atopic skin of the cosmetics, the following experiment was conducted on 15 patients who were treated by atopic skin. The test sample was applied to the whole body by dividing the right side and the left side by the double-blinded test, but the use of other moisturizers that could affect the effect of the test sample was prohibited as much as possible. The effects after 1, 2, 3, and 4 weeks of application of the test sample were calculated according to Equation 1 by SCORAD (SCORAD: SCORing Atopic Dermatitis) measurement and the results are shown in Table 11 below.

1) Criteria

① Extent criteria ： Area = damage area / 100 intensity criteria-erythema (1/2/3) Edema (1/2/3)

Exudate (1/2/3)

-Skin peeling (1/2/3)

Taekwondo degree (1/2 八 3)

-Drying degree (1/2/3)

③ Subjective standard

Itching (1 ~ 10)

Insomnia (1 ~ 10)

[Equation 1]

Table 12

It can be seen from Table 12 that the cosmetic composition of Formulation Example 3 containing isoseconatapasolide of the present invention is superior in atopic skin improvement effect than Comparative Formulation Example 3. After 4 weeks, the result showed improvement of 80.3%, and the improvement rate of atopic skin was shown in FIG. 14. Reference

JP5307369 Β2

Claims

[Range of request]

[Claim 1]

A cosmetic composition for inhibiting and alleviating itching, containing isosecotanaparthol ide represented by the following formula [1] as an active ingredient.

Formula [1] ᅳ

[Claim 2]

A cosmetic composition for improving atopic dermatitis, containing isosecotanapartholide (Isosecotanaparthol ide) represented by the following formula [1] as an active ingredient.

Chemical formula [1]

[Claim 3]

The cosmetic composition according to claim 1 or 2, wherein the isosecotanapartholide is contained in an amount of 0.0001 to 0.5% by weight based on the total weight of the cosmetic composition.

[Claim 4]

The cosmetic composition according to claim 1 or 2, wherein the isosecotanapartholide is separated from the leaves.

[Claim 5]

The cosmetic composition according to claim 1 or 2, wherein the cosmetic composition is a flexible longevity, nourishing cosmetics, essence, nutrition lotion, nutrition cream, eye cream, massage cream, cleansing cream, cleansing products, cleansing water, powder, pack, hair cosmetics Cosmetic composition characterized in that the body lotion, body cream, body oil, body essence or at least one formulation selected from the group consisting of a body cleanser.