JP7417347B2 - Chronic keratinized eczema improving agent - Google Patents

Description

TECHNICAL FIELD The present invention relates to an agent for improving chronic hyperkeratotic eczema that exhibits an excellent improvement effect on chronic hyperkeratotic eczema.

Healthy skin maintains a smooth skin surface through proper skin turnover. However, when the skin is repeatedly subjected to mechanical stimulation such as pressure or friction, inflammation occurs at the skin site, and melanin production, thickening and dryness of the stratum corneum progress, and darkening may occur. A skin condition in which darkening is caused by thickening and dryness of the stratum corneum is called chronic keratotic eczema. Chronic keratotic eczema is a symptom that is often seen in areas of the skin that are subject to repeated mechanical stimulation in daily life, such as elbows and knees. In chronic keratotic eczema, the thickened keratin has a reduced water content, causing bacterial infection, and the darkened skin worsens the appearance and becomes a factor that lowers the quality of life of consumers.

Conventionally, it has been known that emulsified cosmetics containing urea and trehalose are effective for softening keratin sclerosis sites on elbows and knees (see Patent Document 1). However, the emulsified cosmetic described in Patent Document 1 had a slow improvement effect on chronic keratotic eczema, and was not fully satisfactory when applied to chronic keratotic eczema. In addition, in the medical field, laser treatments have traditionally been used to remove hardened keratin, but chronic keratotic eczema has a reduced turnover function, making it difficult for tissue to regenerate properly after treatment. However, there was a concern that it might actually promote melanin production.

Against the background of such conventional techniques, there is a desire for the development of new formulations that can effectively improve chronic keratotic eczema.

Japanese Patent Application Publication No. 2007-269692

An object of the present invention is to provide an agent for improving chronic hyperkeratotic eczema that exhibits an excellent improvement effect on chronic hyperkeratotic eczema.

The present inventor conducted intensive studies to solve the above problems and found that at least one member selected from the group consisting of (A) urea, (B) glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof. , and (C) at least one selected from the group consisting of tocopherol, retinol, and their derivatives, the synergistic effect of these ingredients will significantly improve the effect of improving chronic keratotic eczema. It was found that the increase in The present invention was completed through further studies based on this knowledge.

That is, the present invention provides the inventions of the following aspects.
Item 1. (A) Urea,
(B) at least one member selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof, and
(C) A chronic keratotic eczema improving agent containing at least one member selected from the group consisting of tocopherol, retinol, and derivatives thereof.
Item 2. Item 2. The chronic keratotic eczema improving agent according to item 1, which contains tocopherol and/or a derivative thereof as the component (C).
Item 3. Item 3. The agent for improving chronic keratotic eczema according to item 1 or 2, which is used to improve symptoms of both thickening and darkening of the stratum corneum in chronic keratotic eczema.

The chronic keratotic eczema improving agent of the present invention can effectively improve symptoms such as thickening of the stratum corneum and darkening caused by chronic keratotic eczema, leading to a healthy skin condition. Furthermore, the chronic keratinized eczema improving agent of the present invention is superior in that melanin production is less likely to be promoted after treatment, since keratinized tissue is not forcibly removed as in laser treatment.

Photos are shown of the condition of the elbow of a test subject suffering from chronic keratotic eczema on the elbow before and one month after application of the cream of Example 5.

The chronic keratotic eczema improving agent of the present invention is at least selected from the group consisting of urea (hereinafter sometimes referred to as component (A)), glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof. 1 type (hereinafter sometimes referred to as component (B)), and at least one type selected from the group consisting of tocopherol, retinol, and their derivatives (hereinafter sometimes referred to as component (C)) It is characterized by containing. Hereinafter, the chronic keratotic eczema improving agent of the present invention will be described in detail.

Component (A) The chronic keratotic eczema improving agent of the present invention contains urea. Urea has been known as a drug for treating keratosis since ancient times, as it has both the effect of retaining water through hydrogen bonds and the effect of removing unnecessary keratin through protein denaturation.

Regarding the urea used in the present invention, its raw materials, manufacturing method, purification method, etc. are not particularly limited, and it may be manufactured by itself through chemical synthesis, or a commercially available product may be used. Examples of commercially available urea products include those manufactured or sold by Takasugi Pharmaceutical Co., Ltd., Showa Kagaku Co., Ltd., Kanto Kagaku Co., Ltd., and the like.

The content of urea in the chronic hyperkeratotic eczema improving agent of the present invention is not particularly limited, but examples include 5 to 25% by weight, preferably 5 to 22% by weight, and more preferably 10 to 20% by weight. .

Component (B) The chronic keratotic eczema improving agent of the present invention contains glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and/or salts thereof. These components have carbon skeletons similar to steroids, and are known to have the effect of blunting immune responses and weakening inflammatory responses.

Glycyrrhizic acid is a well-known drug known to have anti-inflammatory and anti-allergic effects.

The type of glycyrrhizic acid derivative is not particularly limited as long as it is pharmaceutically acceptable, but specific examples include methyl glycyrrhizinate, stearyl glycyrrhizinate, and the like. These glycyrrhizic acid derivatives may be used alone or in combination of two or more.

Salts of glycyrrhizic acid and its derivatives are not particularly limited as long as they are pharmacologically acceptable, but specific examples include alkali metal salts such as sodium salts, potassium salts, and dipotassium salts; ammonium salts; It will be done. These salts of glycyrrhizic acid and its derivatives may be used alone or in combination of two or more.

Glycyrrhetinic acid is a well-known drug known to have anti-inflammatory and anti-allergic effects.

The type of glycyrrhetinic acid derivative is not particularly limited as long as it is pharmaceutically acceptable, but specific examples include pyridoxine glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, monoglucuronide glycyrrhetinate, and the like. These glycyrrhetinic acid derivatives may be used alone or in combination of two or more.

Salts of glycyrrhetinic acid and its derivatives are not particularly limited as long as they are pharmacologically acceptable, but specific examples include alkali metal salts such as sodium salts and potassium salts; ammonium salts. These salts of glycyrrhetinic acid and its derivatives may be used alone or in combination of two or more.

In the chronic keratinizing eczema improving agent of the present invention, component (B) includes glycyrrhizic acid, a salt of glycyrrhizic acid, a derivative of glycyrrhizic acid, a salt of a derivative of glycyrrhizic acid, glycyrrhetinic acid, a salt of glycyrrhetinic acid, a derivative of glycyrrhetinic acid. , and salts of glycyrrhetinic acid derivatives, one type may be selected and used, or two or more types may be used in combination.

Among these components (B), from the viewpoint of further improving the effect of improving chronic keratotic eczema, glycyrrhizic acid, derivatives thereof, and/or salts thereof, and more preferably glycyrrhizic acid and/or its salts are preferred. Salts, even more preferably dipotassium glycyrrhizinate or monoammonium glycyrrhizinate, particularly preferably monoammonium glycyrrhizinate.

The content of component (B) in the chronic keratotic eczema improving agent of the present invention is not particularly limited, but is, for example, 0.1 to 3% by weight, preferably 0.2 to 2% by weight, More preferably, it is 0.3 to 1% by weight.

In the chronic keratotic eczema improving agent of the present invention, the ratio of component (A) and component (B) is not particularly limited, and may be adjusted as appropriate within the above-mentioned content range of component (A) and component (B). However, from the viewpoint of further improving the effect of improving chronic keratotic eczema, the total amount of component (B) is 0.5 to 30 parts by weight, preferably 1 part by weight, per 100 parts by weight of component (A). -20 parts by weight, more preferably 1.5-10 parts by weight.

Component (C) The chronic keratotic eczema improving agent of the present invention further contains at least one selected from the group consisting of tocopherol, retinol, and derivatives thereof. Hereinafter, among component (C), tocopherol and/or its derivatives may be referred to as component (C-1), and retinol and/or its derivatives may be referred to as component (C-2). .

Among the components (C-1), tocopherol is a well-known component also known as vitamin E. The tocopherol used in the present invention may be either d-form or dl-form, and may have any of α, β, γ, and δ structures. Specifically, the tocopherol used in the present invention includes d-α-tocopherol, d-β-tocopherol, d-γ-tocopherol, d-δ-tocopherol, l-α-tocopherol, l-β-tocopherol, Examples include l-γ-tocopherol, l-δ-tocopherol, and mixtures thereof such as dl-α-tocopherol, dl-β-tocopherol, dl-γ-tocopherol, and dl-δ-tocopherol.

Among components (C-1), the tocopherol derivative is a component that has the same skeleton as tocopherol and is obtained by adding a substituent to tocopherol.

Like tocopherol, the tocopherol derivative used in the present invention may be either the d-form or the dl-form, and may have any of the α, β, γ, and δ structures.

The type of tocopherol derivative is not particularly limited as long as it is pharmaceutically acceptable, but examples include esters of tocopherol and organic acids. Specific examples of the ester of tocopherol and an organic acid include tocopherol acetate, tocopherol nicotinate, tocopherol succinate, tocopherol linolenic acid ester, and the like. These tocopherol derivatives may be used alone or in combination of two or more.

These (C-1) components are not particularly limited in their raw materials, production methods, purification methods, etc., and may be isolated and purified from animals or the like, or commercially available products may be used. Commercially available products containing component (C-1) include those manufactured by Riken Vitamin Co., Ltd., Eisai Co., Ltd., Eisai Food Chemical Co., Ltd., DSM Nutrition Japan Co., Ltd., Tama Biochemical Co., Ltd., Okami Chemical Co., Ltd., etc. Includes products that are on sale.

In the chronic keratotic eczema improving agent of the present invention, as component (C-1), one type may be selected from tocopherol and tocopherol derivatives, or two or more types may be used in combination. Good too.

Among these components (C-1), preferred are tocopherol derivatives, more preferably tocopherol acetate, from the viewpoint of further improving the effect of improving chronic keratotic eczema.

Among the components (C-2), retinol is a type of vitamin A, and is also sometimes referred to as vitamin A alcohol.

Among components (C-2), the retinol derivative is a component that has the same skeleton as retinol and is obtained by adding a substituent to retinol. The type of retinol derivative is not particularly limited as long as it is pharmaceutically acceptable, but examples include esters of retinol and fatty acids, esters of retinol and acetic acid (i.e., retinol acetate), and retinol oxides. , and esters of the oxides.

Specific examples of esters of retinol and fatty acids include esters of retinol and fatty acids having 1 to 30 carbon atoms, preferably 2 to 18 carbon atoms. More specifically, esters of retinol and fatty acids include retinol acetate, retinol propionate, retinol butyrate, retinol octylate, retinol laurate, retinol palmitate, retinol stearate, and retinol myristic acid. Examples include ester, retinol oleate, retinol linolenic acid ester, and retinol linoleic acid ester. These esters of retinol and fatty acids may be used alone or in combination of two or more.

Specific examples of retinol oxides include retinoic acid (sometimes referred to as "tretinoin"), retinal, and the like. These retinol oxides may be used alone or in combination of two or more.

Specifically, esters of retinol oxides include methyl retinoate, ethyl retinoate, retinol retinoate, tocopherol retinoate (tocopherol may be any of α, β, γ, or δ), etc. can be mentioned. These esters of retinol oxides may be used alone or in combination of two or more.

These (C-2) components are not particularly limited in their raw materials, production methods, purification methods, etc., and may be isolated and purified from animals or the like, or commercially available products may be used. Commercially available products of component (E) include, for example, products manufactured or sold by Riken Vitamin Co., Ltd., DSM Nutrition Japan Co., Ltd., Oka Pharmaceutical Co., Ltd., BASF Japan Co., Ltd., and the like.

In the chronic keratotic eczema improving agent of the present invention, as component (C-2), one type may be selected from retinol and retinol derivatives, or two or more types may be used in combination. Good too.

Furthermore, in the present invention, retinol and/or its derivative used as component (C-2) may be dissolved in oil such as vegetable oil. Such a solution of retinol and/or its derivatives in oil is known as "vitamin A oil." Vitamin A oil can be produced, for example, according to the method described in the Japanese Pharmacopoeia. Vitamin A oil usually has a content of retinol and/or its derivatives of 100,000 to 2,000,000 I.U./g, preferably 500,000 to 1,700,000 I.U./g, and more preferably 500,000 to 1,700,000 I.U./g. One million I.U./g can be used. In addition, in this specification, the unit "I.U." of content of retinol and/or its derivative shows an international unit.

Among these components (C-2), from the viewpoint of further improving the effect of improving chronic keratotic eczema, retinol derivatives, more preferably esters of retinol and fatty acids, particularly preferably retinol palmitic acid. Examples include esters.

In the chronic keratinizing eczema improving agent of the present invention, the (C) component includes tocopherol, a tocopherol derivative (hereinafter referred to as (C-1 component)), retinol, and a retinol derivative (hereinafter referred to as (hereinafter referred to as (C-2 component)). One type may be selected and used from these, or two or more types may be used in combination.

From the viewpoint of further improving the improvement effect of chronic keratotic eczema, it is preferable that the component (C) contains at least the component (C-1), and the component (C-1) and (C-2). It is more preferable that both components are included. More specifically, component (C) preferably contains at least a tocopherol derivative, and more preferably both a tocopherol derivative and a retinol derivative.

The content of component (C) in the chronic keratotic eczema improving agent of the present invention is not particularly limited, and is set as appropriate depending on the type of component (C) used, within a range that achieves the effects of the present invention. do it.

Specifically, when using component (C-1) as component (C), the content of component (C-1) in the chronic keratotic eczema improving agent of the present invention is, for example, 0. .001 to 10% by weight, preferably 0.01 to 5% by weight, more preferably 0.1 to 3% by weight, even more preferably 0.5 to 3% by weight, particularly preferably 0.5 to 2% by weight. Can be mentioned.

In addition, if component (C-2) is used as component (C), the content of component (C-2) in the chronic keratotic eczema improving agent of the present invention, for example, Per 100g of the keratinized eczema improving agent, the component (C-2) is 0.1 to 10 million I.D. U. , preferably 10,000 to 5 million I.P. U. , more preferably 100,000 to 3 million I.P. U. , more preferably 100,000 to 1.5 million I.P. U. , particularly preferably from 250,000 to 1,000,000 I.P. U. can be mentioned.

In addition, when using vitamin A oil as component (C-2), the content of vitamin A oil in the chronic keratotic eczema improving agent of the present invention is as follows: Depending on the amount, the content of component (C-2) in the chronic keratotic eczema improving agent of the present invention may be set so as to satisfy the above-mentioned content. Specifically, 1 million I. U. When using vitamin A oil containing /g of retinol and/or its derivatives, the content of vitamin A oil in the chronic keratotic eczema improving agent of the present invention is 0.001 to 10% by weight, It is preferably set at 0.01 to 5% by weight, more preferably 0.1 to 3% by weight, even more preferably 0.1 to 1.5% by weight, particularly preferably 0.25 to 1% by weight.

In the chronic keratotic eczema improving agent of the present invention, the ratio of component (A) to component (C) is not particularly limited, and the ratio of component (A) to component (C) described above is not limited depending on the type of component (C) used. It may be appropriately set within the content of component (C).

For example, when using component (C-1), the total amount of component (C-1) per 100 parts by weight of component (A) is considered to further improve the effect of improving chronic keratotic eczema. 0.5 to 30 parts by weight, preferably 2.5 to 30 parts by weight, and more preferably 2.5 to 20 parts by weight.

For example, when using component (C-2), the total amount of component (C-2) per gram of component (A) should be increased from the perspective of further improving the effect of improving chronic keratotic eczema. 0.5 million to 300,000 I. U. , preferably 05,000 to 150,000 I.P. U. , more preferably 12,500 to 100,000 I. U. can be mentioned.

Ingredient (D) The chronic keratotic eczema improving agent of the present invention contains, in addition to the above-mentioned (A) to (C) ingredients, γ-oryzanol (hereinafter sometimes referred to as (D) ingredient). ) may be included. By including component (D) in this way, it becomes possible to improve the improvement effect on chronic keratotic eczema even more effectively.

γ-oryzanol is an ester of ferulic acid and a triterpene alcohol, or an ester of ferulic acid and a sterol. In the present invention, as component (D), either an ester of ferulic acid and a triterpene alcohol or an ester of ferulic acid and a sterol may be used alone, or they may be used in combination. Suitable examples of component (D) used in the present invention include those containing cycloartenyl ferulate (C ₄₀ H ₅₈ O ₄ ), more preferably those containing 95% by weight or more of cycloartenyl ferulate, especially Preferred examples include those containing 98% by weight or more of cycloartenyl ferulate.

The CAS registration number of γ-oryzanol is represented by "11042-64-1". The γ-oryzanol used in the present invention may include oryzanol A (CAS registration number [21238-33-5]), oryzanol C (CAS registration number [469-36-3]), and the like.

Regarding γ-oryzanol used in the present invention, its raw material, manufacturing method, purification method, etc. are not particularly limited, and examples thereof include those isolated and purified from rice bran or the like.

Furthermore, γ-oryzanol is manufactured or sold by, for example, Oryza Yuka Co., Ltd., Tsukino Foods Co., Ltd., Wako Pure Chemical Industries, Ltd., Riken Vitamin Co., Ltd., Okayasu Shoten Co., Ltd., etc., and is used in the present invention. These commercially available products can also be used as γ-oryzanol in chronic keratinized eczema improving agents.

When the chronic keratotic eczema improving agent of the present invention contains component (D), its content is not particularly limited, but for example, 0.01 to 10% by weight, preferably 0.1 to 5% by weight, More preferably 0.5 to 2% by weight, particularly preferably 0.75 to 1.5% by weight.

When the chronic keratotic eczema improving agent of the present invention contains component (D), the ratio of component (A) to component (D) is not particularly limited, and the ratio of component (A) to component (D) described above is not particularly limited. However, from the viewpoint of further improving the effect of improving chronic keratotic eczema, the total amount of component (D) should be set at 0.5 parts by weight per 100 parts by weight of component (A). ~50 parts by weight, preferably 2.5 to 20 parts by weight, more preferably 3.5 to 15 parts by weight.

Polyhydric Alcohol The chronic keratotic eczema improving agent of the present invention may contain a polyhydric alcohol, if necessary, in order to improve moisturizing properties.

Polyhydric alcohols are not particularly limited as long as they are pharmaceutically acceptable, but examples include ethylene glycol, 1,3-butylene glycol, propylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol, polypropylene glycol, and glycerin. can be mentioned. These polyhydric alcohols may be used alone or in combination of two or more.

When the chronic keratotic eczema improving agent of the present invention contains a polyhydric alcohol, its content may be appropriately set depending on the formulation form, etc., but is preferably 0.5 to 50% by weight, for example. is 1 to 30% by weight, more preferably 2 to 20% by weight.

Surfactant The external composition of the present invention also contains a surfactant to solubilize or emulsify component (C) and optionally added component (D) to form a desired formulation. May be included. The surfactant is not particularly limited as long as it is pharmaceutically acceptable, and nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants may be used. However, nonionic surfactants are preferred.

Specifically, the surfactants include POE (10 to 50 mol) phytosterol ether, POE (10 to 50 mol) dihydrocholesterol ether, POE (10 to 50 mol) 2-octyl dodecyl ether, POE (10 to 50 mol) moles) decyltetradecyl ether, POE (10-50 moles) oleyl ether, POE (2-50 moles) cetyl ether, POE (5-50 moles) behenyl ether, POE (5-30 moles) polyoxypropylene (5-50 moles) 30 moles) 2-decyltetradecyl ether, POE (10 to 50 moles) polyoxypropylene (2 to 30 moles) polyoxyethylene alkyl ethers such as cetyl ether, phosphoric acids and phosphates of these (POE cetyl ether phosphate) polyoxyethylene sorbitan fatty acid esters such as POE (20-60 moles) sorbitan monooleate, POE (20-60 moles) sorbitan monostearate, POE (10-60 moles) sorbitan monoisostearate, POE (10-80 mol) glyceryl monoisostearate, POE (10-30 mol) glyceryl monostearate, POE (20-100 mol)/polyoxypropylene modified silicone, POE/alkyl modified silicone, polyethylene glycol monolaurate, mono Polyethylene glycol palmitate, polyethylene glycol monostearate, polyethylene glycol dilaurate, polyethylene glycol dipalmitate, polyethylene glycol distearate, polyethylene glycol dioleate, polyethylene glycol diricinoleate, polyoxyethylene hydrogenated castor oil (5-100), Examples include glycerin fatty acid esters (glyceryl monostearate, etc.), hydrogenated soybean phospholipids, hydrogenated lanolin alcohol, and the like. These surfactants may be used alone or in combination of two or more.

When the chronic keratotic eczema improving agent of the present invention contains a surfactant, the content may be appropriately set depending on the formulation form, etc., but is preferably 0.1 to 30% by weight, for example. is 0.5 to 20% by weight, more preferably 1 to 15% by weight.

Other Components The chronic keratotic eczema improving agent of the present invention may contain other pharmacological components in addition to the above-mentioned components, if necessary. Such pharmacological ingredients include, for example, antihistamines (diphenhydramine, diphenhydramine hydrochloride, etc.), local anesthetics (procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, meprilcaine or salts thereof, orthocaine, oxesazein, oxypolyenthoxy) decane, rotoextract, percaminpase, tesitdesitin, etc.), anti-inflammatory agents (indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promoting ingredients (nonylic acid vanillylamide, nicotinic acid benzyl ester) , capsaicin, chili pepper extract, etc.), cooling agents (menthol, camphor, borneol, peppermint water, peppermint oil, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, etc.), and the like.

In addition, the chronic keratotic eczema improving agent of the present invention may contain base materials and additives in addition to the above-mentioned components, as necessary, in order to obtain a desired formulation form. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable, but examples include water, aqueous bases such as lower alcohols (ethanol, isopropanol, etc.); Flower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil, peanut oil, lard, squalane, fish oil, etc.), mineral oil (liquid paraffin, paraffin, gelled hydrocarbons, petrolatum, etc.), waxes, etc. Waxes (beeswax, carnauba wax, candelilla wax, ceresin, rice wax, microcrystalline wax, etc.), ester oils (isopropyl myristate, isopropyl adipate, diethyl sebacate, isopropyl sebacate, isopropyl palmitate, cetyl palmitate, olein) ethyl acid, etc.), fatty acid alkyl esters, fatty acids (stearic acid, oleic acid, palmitic acid, behenic acid, linoleic acid, lanolin, etc.), fatty acid esters (cetyl palmitate, isopropyl palmitate, ethyl linoleate, etc.), higher alcohols ( stearyl alcohol, cetanol, behenyl alcohol, myristyl alcohol, oleyl alcohol, hexadecyl alcohol, lanolin alcohol, etc.), cholesterol, glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, silicone oil (dimethylpolysiloxane, cyclic silicone, etc.) oily bases such as; preservatives (methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), flavoring agents (citral, 1,8-cyonel, citronellal, farnesol, etc.), colorants (tar pigments ( Brown No. 201, Blue No. 201, Yellow No. 4, Yellow No. 403, etc.), cacao pigment, chlorophyll, aluminum oxide, etc.), thickening agents (carboxyvinyl polymer, hypromellose, polyvinylpyrrolidone, sodium alginate, ethylcellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan, etc.), pH adjusters (phosphoric acid, hydrochloric acid, citric acid, sodium citrate, succinic acid, tartaric acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agents (dl- Sodium pyrrolidonecarboxylate solution, D-sorbitol solution, macrogol, etc.), stabilizers (dibutylhydroxytoluene, butylhydroxyanisole, sodium edetate, sodium metaphosphate, L-arginine, L-aspartic acid, DL-alanine, glycine) , sodium erythorbate, propyl gallate, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidants, ultraviolet absorbers, chelating agents, adhesives, buffers, solubilizing agents, solubilizers Examples include additives such as agents and preservatives.

Method for producing a chronic keratinizing eczema improving agent The chronic keratinizing eczema improving agent of the present invention comprises components (A) to (C), and if necessary, component (D) and other components, in its formulation form. They are prepared by mixing the desired amounts in the appropriate manner.

Formulation/Uses The formulation of the chronic keratotic eczema improving agent of the present invention is not particularly limited as long as it can be applied transdermally, and may be liquid, solid, semi-solid (gel, ointment, etc.). It may be in any of the following forms: paste form, paste form), etc.

Moreover, the chronic keratotic eczema improving agent of the present invention may be in any formulation form, such as a skin external medicine, a cosmetic, a skin cleansing agent, etc., as long as it is applied to the skin. Specifically, the formulation forms of the chronic keratotic eczema improving agent of the present invention include creams, ointments, emulsions, gels, oils, liquids, lotions, liniments, aerosols, patches, and packs. Cosmetics such as ointments, creams, milky lotions, lotions, lotions, packs, and gels; Skin cleansers such as body shampoos, hair shampoos, and conditioners. Among these formulations, pharmaceuticals for external use on the skin are preferred, and creams, ointments, emulsions, and lotions are more preferred.

The agent for improving chronic hyperkeratotic eczema of the present invention is applied to a skin site exhibiting chronic hyperkeratotic eczema and is used to improve chronic hyperkeratotic eczema. Chronic keratotic eczema is often observed on body parts such as elbows and knees, and is a skin symptom accompanied by thickening and darkening of each layer. The agent for improving chronic keratotic eczema of the present invention can improve both the symptoms of thickening and darkening of the stratum corneum in chronic keratinizing eczema. Furthermore, the chronic keratotic eczema improving agent of the present invention can also be applied to body parts such as elbows and knees that do not exhibit chronic keratotic eczema, for the purpose of preventing chronic keratotic eczema.

Further, the dose of the chronic keratotic eczema improving agent of the present invention may be appropriately determined depending on the formulation form, the severity of symptoms, and the like. As an example of the dosage of the chronic keratotic eczema improving agent of the present invention, the amount of the component (A) to be applied per 1 cm ² of skin is approximately 0.1 to 3 mg per day. The frequency may be several times, but the frequency is not limited to this range.

EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.

Reference test example 1: Evaluation of tyrosinase activity inhibition rate
1. Evaluation method According to the conditions shown in Table 1, 5mM L-DOPA (dihydroxy-L-phenylanine) aqueous solution was added to 50mM phosphate buffer (pH 6.5). Next, each component (L-ascorbic acid, monoammonium glycyrrhizinate, γ-oryzanol (cycloartenyl ferulate (C ₄₀ H ₅₈ O ₄ ) content: 99.4% by weight), vitamin A oil (retinol palmitate ester) After adding and stirring a DMSO (dimethyl sulfoxide) solution of 1 million I.U./g or tocopherol acetate), an enzymatic reaction was started by adding a tyrosinase aqueous solution (tyrosinase content: 3.91 units). Temperature: 37°C). Fifteen minutes after the start of the enzyme reaction, absorbance (475 nm) was measured using a microplate reader. The inhibition rate of tyrosinase activity at multiple concentrations of each component was measured by serial dilution, and the 50% inhibitory concentration (IC50, w/v%) was calculated. The tyrosinase activity inhibition rate (%) was calculated using the following formula.

2. Evaluation results The results obtained are shown in Table 2. As a result, it was confirmed that L-ascorbic acid and monoammonium glycyrrhizinate can inhibit tyrosinase activity at lower concentrations. Furthermore, γ-oryzanol, tocopherol acetate, and vitamin A oil had a certain tyrosinase activity inhibiting effect, but the results were lower than those of L-ascorbic acid and monoammonium glycyrrhizinate.

Test Example 1: Evaluation of effects on melanin production and brightness
1. Evaluation method <Preparation of test sample>
Creams (oil-in-water emulsified creams) having the composition shown in Table 3 were prepared (Examples 1 to 5, Comparative Examples 1 to 3, and Reference Examples 1 to 2). Specifically, a cream was obtained by mixing an aqueous component and an oil component, heating and dissolving them as necessary, stirring them, and then cooling them. In addition, vitamin A oil contains 1,000,000 I.D. of retinol palmitate per gram. U. Furthermore, γ-oryzanol containing 99.4% by weight of cycloartenyl ferulate (C ₄₀ H ₅₈ O ₄ ) was used. The following tests were conducted using each of the obtained creams as test samples.

<Test method>
Tested according to the test method of "Melanin production inhibitor evaluation method using reconstructed epidermis model" listed in "Moisturizing, whitening, anti-wrinkle, anti-oxidant evaluation, experimental method manual" (Fragrance Journal, published February 2012) I did it.

As a cultured skin model containing melanocytes, a MEL-300 kit (MEL-300-A, Kurashiki Boseki Co., Ltd.) was used. During the test period, the cells were maintained and cultured in a CO ₂ incubator (37° C., 5% CO ₂ ) using EPI-100LLMM long-term maintenance medium (Kurashiki Boseki Co., Ltd.).

After the melanocytes were transferred to a 6-well plate and precultured, the test sample was applied. The test sample was applied from the stratum corneum side. After 2 weeks of continuous culture, melanin quantification and brightness measurements were performed based on the absorbance and color tone of melanocytes. Furthermore, in order to confirm the presence or absence of cytotoxicity due to the application of the test sample, cell viability was evaluated using the Alamar Blue method, and corrections were made for "melanin production amount" and "brightness."

-Measurement of melanin production amount Melanocytes were transferred to a tube and washed using PBS (-). Furthermore, after washing with 5% trichloroacetic acid, ethanol/diethyl ether solution, and diethyl ether in this order, 1 mol/L aqueous sodium hydroxide solution was added to dissolve melanin contained in melanocytes by heating (100°C, 10 minutes). )did. Absorbance at 405 nm was measured using a microplate reader. "Melanin production amount" was calculated from the measured values based on a calibration curve created using synthetic melanin (Sigma-Aldrich Japan Co., Ltd.). Next, the relative value when the melanin production amount of Comparative Example 1 was set to "100" was calculated as "melanin production rate" (%) (rounded to the first decimal place).

- Measurement of brightness The brightness (L value) of melanocytes was measured from the bottom side using a spectrophotometer (CR-13 (Konica Minolta Holdings, Inc.). Measurement was performed 5 times, and the average value was determined. Next, the relative value when the brightness of Comparative Example 1 was set to "100" was calculated as a "brightness improvement rate" (%) (rounded to the first decimal place).

-Evaluation of cell viability using Alamar Blue method EPI-100LLMM long-term maintenance medium containing 10% Alamar Blue reagent was dispensed into a 24-well plate. MEL-300 was transferred to this plate and cultured for 2 hours. The fluorescence intensity (Ex./Em.=544 nm/590 nm) of the culture supernatant was measured. The cell survival rate was calculated as Index (%) when the fluorescence intensity of Comparative Example 1 was set as "100". The results were all 99-105%. Based on this cell survival rate, the values of "melanin production amount" and "brightness" were corrected.

2. Evaluation results The results obtained are shown in Table 3. Comparative Example 2 containing only urea showed no significant difference from the control (Comparative Example 3) in melanin production amount and brightness. Furthermore, Comparative Example 1 in which monoammonium glycyrrhizinate, which has the effect of inhibiting tyrosinase activity, was combined with urea did not have sufficient effects in terms of melanin production and brightness. On the other hand, in Example 1 containing vitamin A oil together with urea and monoammonium glycyrrhizinate, it was possible to suppress the amount of melanin production and improve brightness. Furthermore, in Example 2 containing urea, monoammonium glycyrrhizinate, and tocopherol acetate, the amount of melanin produced was significantly reduced, and a significant improvement in brightness was also observed. Furthermore, in Examples 3 to 5 containing γ-oryzanol in addition to urea, monoammonium glycyrrhizinate, and vitamin A oil and/or tocopherol acetate, the amount of melanin production was significantly reduced, and the brightness was further reduced. A significant improvement was observed.

Test Example 3: Evaluation of improvement effect on chronic keratotic eczema
1. Evaluation method A cream (oil-in-water emulsion cream) having the composition shown in Table 4 was prepared in the same manner as in Test Example 1 (Examples 2, 4, 5, Comparative Examples 1, 2, 4 to 7). In addition, vitamin A oil contains 1,000,000 I.D. of retinol palmitate per gram. U. Furthermore, γ-oryzanol containing 99.4% by weight of cycloartenyl ferulate (C ₄₀ H ₅₈ O ₄ ) was used.

Using each cream, a clinical evaluation was conducted on 9 subjects who had chronic keratotic eczema on their elbows and were concerned about thickening and darkening of the horny layer of their elbows. One cream per subject was applied to the elbow once a day at a dose of approximately 1.5 mg/cm ² of skin for one month. One month later, regarding satisfaction with the improvement of chronic keratotic eczema, ``the thickening and darkening of the horny layer of the elbow were improved'' was rated ``10,'' and ``the thickening and darkening of the horny layer of the elbow were not improved.'' It was evaluated by the VAS method (Visual Analogue Scale) with "1". Further, a relative value was calculated as an "improvement rate" (%) when the VAS score of Comparative Example 1 was set to "100" (rounded to the first decimal place).

2. Evaluation results The results obtained are shown in Table 4. Further, FIG. 1 shows photographs taken of the condition of the elbow before application of Example 5 and one month after application. In Comparative Example 2 containing urea alone, the thickening and darkening of the stratum corneum could not be sufficiently improved, and the effect of improving chronic keratotic eczema was not satisfactory. In addition, Comparative Example 1, which combined urea and monoammonium glycyrrhizinate, Comparative Example 5, which combined urea and vitamin A oil, and Comparative Example 6, which combined urea and tocopherol acetate, had the same level as Comparative Example 1, which used urea alone. Only the effects of Furthermore, in Comparative Example 4 in which monoammonium glycyrrhizinate and tocopherol acetate were combined, and in Comparative Example 7 in which monoammonium glycyrrhizinate was combined with vitamin A oil, compared to Comparative Example 2 in which urea alone was used, the effects of chronic keratotic eczema were significantly reduced. The improvement effect was poor. On the other hand, in Example 2 containing urea, monoammonium glycyrrhizinate, and tocopherol acetate, an excellent effect of improving chronic keratotic eczema was observed. Furthermore, in Examples 4 and 5 containing vitamin A oil and/or γ-oryzanol in addition to these ingredients, the effect of improving chronic keratotic eczema was significantly excellent. The improvement effect on keratotic eczema was markedly increased.

Formulation Examples Chronic keratotic eczema improving agents shown in Tables 5 to 7 were prepared. The chronic keratinizing eczema improving agents shown in Table 5 are cream formulations (oil-in-water emulsion creams), the chronic keratinizing eczema improving agents shown in Table 6 are liquid formulations, and the chronic keratinizing eczema improving agents shown in Table 5 are liquid formulations. It is a gel agent. When each of the obtained chronic keratotic eczema-improving agents was evaluated for its effect on improving chronic keratotic eczema in the same manner as in Test Example 2, an excellent effect on improving chronic keratotic eczema was observed.

Claims (2)

(A) Urea,
(B) at least one member selected from the group consisting of glycyrrhizic acid, its salts, methyl glycyrrhizinate, and stearyl glycyrrhizinate;
(C) at least one member selected from the group consisting of tocopherol and esters of tocopherol and organic acids, and
(D) Chronic keratotic eczema improving agent containing gamma oryzanol (however, citric acid, cetostearyl alcohol, lanolin, DL-alanine, L-arginine, reduced maltose starch syrup, xanthan gum, glycine, glycerin, cholesterol, silicone resin) , squalane, glyceryl stearate, propylene glycol stearate, soy lecithin, sodium lactate, myristic acid and a cream containing octyldodecyl; polyoxyl 40 stearate, self-emulsifying glyceryl monostearate, purified soy lecithin, lactic acid, triethanolamine. , glycine, methyl paraoxybenzoate, butyl paraoxybenzoate, 1,3-butylene glycol, stearic acid, cetanol, squalane, methylpolysiloxane, and a cream containing medium chain fatty acid triglyceride; cetostearyl alcohol, white petrolatum, squalane, A cream containing light liquid paraffin, isopropyl myristate, polysorbate 60, self-emulsifying glyceryl monostearate, polyoxyethylene hydrogenated castor oil, dimethylpolysiloxane, propylene glycol, glycerin, xanthan gum, triethanolamine, methylparaben, and propylparaben. ,except for) . The agent for improving chronic keratotic eczema according to claim 1, which is used to improve symptoms of both thickening and darkening of the stratum corneum in chronic keratotic eczema.