WO2006121210A1

WO2006121210A1 - Agent for improving skin condition

Info

Publication number: WO2006121210A1
Application number: PCT/JP2006/309975
Authority: WO
Inventors: Isao Serizawa; Hideki Goto; Hajime Ono; Hiroyuki Miyazaki
Original assignee: Takata Seiyaku Co., Ltd.
Priority date: 2005-05-13
Filing date: 2006-05-11
Publication date: 2006-11-16
Also published as: JPWO2006121210A1

Abstract

An agent for improving skin condition comprising a complex (associate) of hyaluronic acid and zinc.

Description

Skin condition improver

Technical field

The present invention has a skin barrier function improving action, a moisturizing action, and a rough skin improving action comprising a zinc hyaluronate complex (aggregate) as an active ingredient.

The present invention relates to a skin condition improving agent.

More specifically, the inclusion of the hyaluronic acid zinc complex (aggregate) makes it possible to prevent abnormal skin growth due to a decrease in the epidermal function of the skin, and to improve the skin barrier function. Skin barrier dysfunction that improves skin barrier dysfunction caused by rubbing Skin prevention and improvement of skin roughness with excellent effects suitable for topical preparations It relates to a skin condition improving agent that maintains its normal function and normalizes.

Background art

In recent years, external or internal stresses such as changes in the environment (depletion of the ozone layer, global warming, environmental pollution, etc.), aging, diseases, changes in dietary habits, mental stress and sunburn (effect of ultraviolet rays on the skin) Due to an increase in factors, skin troubles and worries are occurring frequently. In this way, the skin is subjected to various physical, chemical and biological external stimuli.

Skin is anatomically divided into epidermis, dermis, and subcutaneous tissue, of which the epidermis is composed of a basal layer, a spiny layer, a granular layer, and a horny layer. The stratum corneum of the epidermis is very thin and is less than 20 m thick, which causes dryness and rough skin due to the above factors.

Deterioration of skin symptoms is accompanied by sputum, palpation, fluid leaching, skin peeling, scab In many cases, healthy skin cannot be maintained without comprehensive improvement effects including these. Conventionally, the use of steroids and internal use of traditional Chinese medicines have been used to comprehensively improve skin symptoms, but these effects are not sufficient.

Originally, the skin has a skin barrier function and protects the living body from the above factors. When this function is reduced, external irritation causes rough skin, skin contamination and various dermatitis. In addition, the decrease in skin barrier function increases the amount of moisture transpiration from the skin, causing dryness (dry skin) and itching.

It has been reported that when skin barrier function declines, moisture transpiration from the skin increases, dry skin symptoms such as skin roughness and increased desquamation are observed.

It is known that the loss of moisture from the skin is more active than that of healthy skin in rough skin symptoms seen in various skin diseases.

. This increase in so-called transepidermal water transpiration (TEWL: Tran s ep ide rma l water los ss) is due to a decrease in the components that are thought to be responsible for moisture retention and barrier functions within the epidermis. Has been considered to be involved. Usually, the skin barrier function is evaluated by the amount of water transpiration from the skin (transepidermal water transpiration; TEWL).

It has been reported that when the skin barrier function is reduced, the skin function is reduced and skin proliferative abnormalities occur. In particular, in the case of elderly people, it takes a long time to recover the reduced skin barrier function, and a novel skin barrier function improving agent that is effective in preventing abnormal skin growth due to a decrease in skin function due to aging. The development of was requested.

Conventionally, many studies have been conducted on substances that improve and prevent rough skin, but research on substances that have an improvement or recovery effect on skin barrier function has not been sufficient, and it has not been possible on skin barrier function. Since there is no clear relationship between the improvement effect and the rough skin improvement / prevention effect, substances with the rough skin improvement / prevention effect do not necessarily have an improvement effect on the skin barrier function.

Moisturizers such as urea and heparin-like substances, barrier function improvers that prevent the evaporation of moisture from the skin, such as ヮ serine, and polymer-coated films against dryness and rough skin as described above, and other hyaluronic acid Mucopolysaccharides or similar substances are included in cosmetics and skin preparations.

However, these are not effective enough, and there is an unpleasant feeling of use such as stickiness, discomfort or irritation. Also, it is not possible to improve the sag due to drying.

On the other hand, chitosan and its derivatives are described as raw materials for cosmetics in JP-A-10-182332 and JP-A-2000-212203, etc., but the skin barrier function improving action and antipruritic effect are described. Is not listed.

There is also a patent application for a skin barrier function improving action using hyaluronic acid, which is a constituent of the present invention, but the skin barrier function improving action is similarly not sufficient.

On the other hand, healthy skin is moist and moist, because the sebum membrane and the stratum corneum are integrated to protect the skin from external stimuli and maintain the moisture of the stratum corneum. is there.

However, due to various causes such as humidity, lowering of temperature, ultraviolet rays, effects of air conditioning, lowering of the new function, etc., the reincarnation rhythm of skin cells may be distorted or sufficient sebum film may not be formed. Moisture required for water cannot be maintained, and it becomes dry and rough.

For this reason, various moisturizers have been proposed to control the moisture on the skin surface to prevent skin dryness. Conventionally, as a moisturizing ingredient, for example, ' In addition to lysine, propylene glycol, 1,3-butylene glycol and other polyhydric alcohols, fat and oil components, amino acids, proteins, polysaccharides, mucopolysaccharides, and the like are used. Among them, hyaluronic acid is a humectant with a very high moisturizing property that is said to have a moisture retention of 6 lg. For example, Japanese Patent No. 25491 19 proposes an external preparation containing hyaluronic acid that eliminates skin discomfort. In addition, Japanese Patent Publication No. 10-7043 proposes a cosmetic material including hyaluronic acid that has good friendliness with the skin.

Patent Document 1 Japanese Patent Laid-Open No. 10-182332

Patent Document 2 Japanese Patent Laid-Open No. 2000-—2203, etc.

Patent Document 3 Patent No. 2549 1 19

Patent Document 4 Japanese Patent Publication No. 10 7043

The present invention has been made in view of the above-described conventional problems, and an object thereof is to provide a skin condition improving agent having an excellent skin barrier function improving action, skin moisturizing action, and rough skin prevention improving action. That is, the present inventors have a skin barrier function improving action useful for preventing epidermal growth abnormalities caused by a decrease in the skin epidermal function, which has no drawbacks of the prior art, is highly stable and suitable for external use, Skin barrier dysfunction that improves skin barrier dysfunction caused by exposure to ultraviolet rays, skin barrier dysfunction inhibiting action and excellent skin roughening prevention, improving skin symptom comprehensively, and improving the skin's original function The purpose is to provide a skin condition improving agent that maintains and normalizes the skin condition.

As a result of intensive investigations, the present inventors have found that an external preparation using a zinc hyaluronate complex (compound) has an excellent skin barrier function improving effect and moisturizing effect; useful as a skin condition improving agent Heading that The present invention has been completed.

In other words, as a result of extensive research on substances that repair and improve skin barrier function, that is, TEWL changes, the hyaluronic acid zinc oxide complex (associate) has been significantly affected by damaged skin barrier function. I found new knowledge to recover.

Furthermore, the present inventors have found that an external preparation using a zinc hyaluronate complex (aggregate) has an excellent effect of suppressing moisture transpiration from the skin.

These individual actions are also confirmed by experimental results that they are excellent as effects that are observed independently. However, by combining these effects, the present invention can be applied to the skin condition. It has been found that it has a particularly excellent effect as an improving agent.

Therefore, the present invention provides a skin condition improving agent comprising a zinc hyaluronate complex (aggregate).

The present invention also provides the use of a zinc hyaluronate complex (associate) for the manufacture of a skin condition improving agent.

The present invention also provides a method for improving skin condition, comprising administering a zinc hyaluronate complex (aggregate) to a patient in need of improvement of skin condition. The invention's effect

According to the present invention, a skin condition improving agent having an excellent skin barrier function improving effect and a moisturizing effect can be provided. Furthermore, it is possible to provide a composition that can achieve both of these effects and a good feeling of use.

The skin condition improving composition of the present invention has an excellent effect of suppressing moisture transpiration from the skin, has a good feeling of use, and has an effect of keeping dry skin healthy. To do. That is, drying of skin due to various causes, for example, dry skin caused by environmental humidity reduction, nutritional disorders, aging, skin diseases, etc. can be improved. The present invention can be used in fields such as pharmaceuticals and cosmetics.

The zinc hyaluronate complex (associate) of the present invention exhibits a higher effect than hyaluronic acid (sodium salt), zinc (chloride) and a simple mixture thereof, and is synergistic by being a complex (associate). Show the effect. In addition, it is more effective than currently used drugs (urea preparations and heparin analog preparations). Brief Description of Drawings

Figure 1 shows the time course of TEWL when a gel base, 0.125%, 0.25%, 0.5%, or 1% zinc hyaluronate complex (aggregate) gel was applied to the skin barrier dysfunction site in Bhubane. It is a graph which shows a change.

Figure 2 shows the AUC of TEWL when a gel base, 0.125%, 0.25%, 0.5%, or 1% zinc hyaluronate complex (associate) gel is applied to the skin barrier dysfunction site in Bhubane. It is a graph to show. Gel base and zinc hyaluronate complex (aggregate) Shows that there is a significant difference at a 1% risk in the gel tendency test (Jonckheere's tendency test).

Fig. 3 shows 1% zinc hyaluronate complex (aggregate) gel, G.3% heparin analog ointment, 2G% urea ointment, gel base or hydrophilic ointment base 6 is a graph showing changes in TEWL over time when an agent is applied.

Fig. 4 shows that 1% zinc hyaluronate complex (aggregate) gel, 0.3% heparin analogue ointment, 20% urea ointment, gel base or hydrophilic ointment base at the skin barrier dysfunction site It is a graph which shows AUC of TEWL when apply | coating. Fig. 5 shows a mixture gel of 1% zinc hyaluronate complex (associate) gel, 0.976% sodium hyaluronate gel, 0.1 66% zinc chloride gel, sodium hyaluronate zinc monochloride FIG. 6 is a graph showing a change with time of TEWL when a gel base or a NaCl-containing gel base is applied. 1% zinc hyaluronate complex (aggregate) As a result of a two-way ANOVA of a gel with a mixture gel of sodium hyaluronate zinc monochloride, 1% at 4, 24 and 96 hours, 5% at 48 hours There is a significant difference.

Fig. 6 shows a mixture of 1% zinc hyaluronate complex (aggregate) gel, 0.976% sodium hyaluronate gel, 0.166% zinc chloride gel, sodium hyaluronate zinc monochloride 6 is a graph showing AUC of TEWL when a gel, gel base or NaCl-containing gel base is applied.

Figure 7 shows the results when gel gel, 0.125%, 0.25%, 0.5%, 0.75%, or 1% zinc hyaluronate complex (aggregate) gel was applied to guinea pigs that induced skin barrier dysfunction due to SLS. 6 is a graph showing changes in TEWL over time.

Figure 8 shows that a gel base, 0.125%, 0.25%, 0.5%, 0.75%, or 1% zinc hyaluronate complex (aggregate) gel was applied to guinea pigs that induced skin barrier dysfunction due to SLS. It is a graph showing the cumulative total of 6 days of TEWL. Gel base and zinc hyaluronate complex (aggregate) There is a significant difference at a 1% risk in the gel tendency test (Jon ckheere tendency test).

Figure 9 shows that guinea pigs that induced skin barrier dysfunction due to SLS were gel base, 0.5%, 1% zinc hyaluronate complex (aggregate) gel, hydrophilic ointment base, 0.3% heparin analog ointment or 3 is a graph showing changes in TEWL over time when 20% urea ointment is applied. ' Figure 10 shows that guinea pigs induced SLS-induced skin barrier dysfunction were gel base, 0.5%, 1% zinc hyaluronate complex (associate) gel, hydrophilic ointment base, 0.3% heparin. 6 is a graph showing the cumulative total of 6 days of TEWL when a similar substance ointment or 20% urea ointment is applied.

Fig. 1 1 shows that 1% zinc hyaluronate complex (aggregate) gel, 0.976% sodium hyaluronate gel, 0.166% zinc chloride gel, hyaluronic acid on guinea pigs induced skin barrier dysfunction by SLS. FIG. 5 is a graph showing changes in TEWL over time when a mixed gel of sodium trichloride or zinc chloride, a gel base, or a NaCl-containing gel base is applied.

Figure 12 shows that guinea pigs induced SLS-induced skin barrier dysfunction with 1% zinc hyaluronate complex (aggregate) gel, 0.976% sodium hyaluronate gel, 0.166% zinc chloride gel, hyaluronic acid. It is a graph showing the cumulative total of TEWL for 6 days when a mixture gel, gel base, or NaCl-containing gel base of sodium trichloride is applied.

Fig. 13 shows that a gel base, 0.125, 0.25, 0.5, 0.75, or 1% zinc hyaluronate complex (aggregate) gel was applied to a guinea pig that induced a skin damage model by SLS. It is a graph showing the change with time of the moisture content of the stratum corneum when applied. The numerical values show the average value and standard error of 15 cases.

Figure 14 shows that guinea pigs that induced the skin damage model due to SLS were loaded with gel base, 1% zinc hyaluronate complex (aggregate), 0.976% sodium hyaluronate gel, or 0.166ZnCl ₂ gel. It is a graph which shows the time-dependent change of a stratum corneum water content when apply | coating. The numerical values show the average value and standard error of 15 cases.

Figure 15 shows the time course of stratum corneum water content when a gel base, 1% zinc hyaluronate complex (aggregate) gel or mixture gel was applied to a guinea pig that induced a skin damage model by SLS. It is a graph. The numerical values show the average straightness and standard error of 15 cases. Figure 16 shows that a gel base, 0.5% zinc hyaluronate complex (aggregate) gel or 1% zinc hyaluronate complex (aggregate) gel was applied to guinea pigs that induced a skin damage model by SLS. It is a graph which shows a time-dependent change of the stratum corneum moisture amount when apply | coating. The numerical values show the average value and standard error of 15 cases.

li l 7 was applied to 0.5% zinc hyaluronate complex (aggregate) gel, 1% zinc hyaluronate complex (aggregate) gel, 0.3% in guinea pigs that induced the skin damage model due to SLS. 2 is a graph showing the change over time of the stratum corneum water content when% heparin-like substance ointment or 20% urea ointment is applied. The numerical values show the average value and standard error of 15 cases. BEST MODE FOR CARRYING OUT THE INVENTION

Zinc hyaluronate complex (aggregate)

The active ingredient of the present invention is a zinc hyaluronate complex (associate). Hyaluronic acid usually exists as a sodium salt and is a macromolecule described by Meyet et al., J, Bio Chem, VoI, 107, 629 (1934). Hyaluronic acid is a highly viscous darcosaminodarlican having alternating / 3 1,3-glucuronic acid component and 3 1,4 -darcosamine component, and its molecular weight is 50 to several million D. Hyaluronic acid is found in all mammalian connective tissues and is present at high levels in the skin, the vitreous of the eye, synovial fluid, ligaments and cartilage tissue. Since hyaluronic acid is a fundamental component of connective tissue, it is biocompatible, biosorbable, and not immunogenic. For this reason, hyaluronic acid performs many biological functions such as lubricity and protection of articular cartilage.

In the zinc hyaluronate complex (associate) of the present invention, the ratio of hyaluronic acid to zinc is a range in which these components have a synergistic effect as a skin barrier function improving agent, and the weight ratio As, hereon Acid: Zinc is in the range of about 5: 1 to 20: 1, preferably about 10: 1. The average molecular weight of the zinc hyaluronate complex (aggregate) used in the present invention is preferably about 100 kD to 2, OO OkD, and more preferably about 400 to 1,200 kD from the viewpoint of stability and formulation design. For example, an average molecular weight of about l OOOkD is preferred. The zinc hyaluronate complex (associate) of the present invention can be produced, for example, by mixing an aqueous solution of sodium hyaluronate with a zinc salt, such as an aqueous solution of zinc chloride (European Patent Specification No- EP0413016).

Zinc hyaluronate complex (aggregate) was not systemically toxic even when administered subcutaneously to rats and mice at a physical maximum dose of 200 mg Z kg.

Additives etc.

When using the above skin barrier dysfunction-improving agent for a topical skin preparation, in addition to the essential ingredients of the present invention, additional ingredients that are conventionally used in cosmetics and Z or the dermatological field are appropriately added as necessary. Can be blended. That is, within the range that does not impair the effects of the present invention, other ingredients that are usually used in topical skin preparations such as cosmetics and pharmaceuticals, such as humectants, oily ingredients, surfactants, vitamins, proteolytic enzymes, Sticky agent, antiseptic, powder, antioxidant, UV absorber, emulsifier, fragrance, cosmetic or pharmaceutical active agent, vitamins, essential fatty acids, sphingolipid, self-suntan agent, sunscreen agent, film A forming polymer, a coloring agent, a facial material, an alcohol, a coloring material, an aqueous component, water, various skin nutrients, and the like can be appropriately blended as necessary. It goes without saying that any additional compound should be understood by a person skilled in the art so that possible additions do not adversely affect or substantially do not adversely affect the advantageous properties of the composition of the invention. And / or the amount will be selected.

Moisturizer. Examples of humectants include glycerin, propylene glycol, polyethylene glycol, polyhydric alcohols such as 1,3-butylene glycol, sugar alcohols such as sorbitol, mannitol, water-soluble substances such as chondroitin sulfate and chitosan. Polymer, urea, sodium lactate, pyrrolidone carboxylic acid, collagen, sodium lactate, d 1 -pyrrolidone carboxylate, ocinine extract, brown sugar extract and chitosan derivative salt, etc. Also, heparin-like substances, collagen, fluorizanol, arylenolic acid, linoleic acid, vitamin E, vitamin D, vitamin A, squalene, squalane, cholesterol, triglyceride And ceramics.

Oil component

Examples of oil components include natural oils such as soybean oil, nutka oil, apogado oil, almond oil, olive oil, cocoa butter, sesame oil, persic oil, castor oil, coconut oil, mink oil, beef tallow, and lard. Hardened oils obtained by hydrogenating these natural fats and oils, synthetic glycerides such as glyceryl myristate, glyceride 2-ethylhexanoate, diglycerides and other fats, jojoba oil, carnauba wax, whale wax , Waxes such as beeswax, lanolin, etc., hydrocarbons such as liquid paraffin, petrolatum, paraffin, mike mouth crystal wax, ceresin, sugelan, pristane, lauric acid, myristic acid, palmitic acid, Stearic acid, behenic acid, oleic acid, linoleic acid, linolenic acid, lanolinic acid, isostearic acid, etc. Higher fatty acids, lauryl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, cholesterol, higher alcohols such as 2-hexyldecanol, jojoba alcohol, cetyl octanoate, myristyl lactate, cetyl lactate, myristin lactate Myristyl acid, Octyl dodecyl myristate, Isopropyl myristate, Isopropyl palmitate, Adipic acid Examples include esters such as sopropyl, butyl stearate, decyl oleate, and cholesterol cholesterol, essential oils, and silicone oils.

Surfactant

Examples of the surfactant include glycerin fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, tetraoleic acid polyoxyethylene sorbitol, polyoxyethylene alkyl ether Polyoxypropylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene castor oil, polyglycerin fatty acid ester, fatty acid monodalise, sucrose fatty acid ester , Nonionic surfactants such as higher fatty acid alkanolamides, Q! —Sodium sodium sulfonate, sodium lauryl sulfate, sodium cetyl sulfate Lithium, sodium polyoxyethylene lauryl sulfate, disodium lauryl sulfosuccinate, linear alkyl benzene sulfonate, branched alkyl benzene sulfonate, alkyl sulfate, alkenyl sulfate, ethylene oxide and / or propylene oxide Alkyl ether carboxylate or alkenyl ether carboxylate with addition of Q! —Sulfo fatty acid ester, amino acid type surfactant, phosphoric ester type surfactant, taurine type surfactant, amide ether sulfate Type surfactants, amphoteric surfactants such as strong l-poxy bene type, aminocarboxylic acid, sulfobetaine type, and cationic surfactants such as quaternary ammonium salts. In terms of safety, nonionic surfactants Preferred.

Vitamins Examples of vitamins include vitamin A, vitamin B, vitamin O, vitamin D, vitamin E, vitamin F, vitamin K, vitamin Ρ, and vitamin U.

Proteolytic enzyme

Examples of the proteolytic enzyme include pepsin, trypsin, chymotrypsin, cathebsin, papain, bromelain, physin and bacteria, yeast, and fungi-derived protease.

Thickener

Examples of the thickener include water-soluble polymer compounds such as carboxyvinyl polymer, carboxymethyl cellulose, polyvinyl alcohol, ruginane, gelatin, xanthan gum, and polyacrylate, and inorganic salts such as chloride chloride. It is done.

Preservative

Examples of the preservative include phenoxyethanol, methyl paraben, ethyl paraben, butyl paraben, sodium benzoate and the like.

powder

Examples of powders include talc, sericite, my strength, kaolin, silica, bentonite, vermiculite, zinc white, mica, mica titanium, titanium oxide, magnesium oxide, zirconium oxide, barium sulfate, bengara, iron oxide , Ultramarine, etc. Examples of other components include fragrances, pigments, and bactericides.

Dosage form

The dosage form of the composition for improving skin barrier function of the present invention is not particularly limited. For example, an ointment, cream, liquid, gel, sol, aqueous solution, alcohol, glycerin / glycol, oil, suspension Examples include mold mouth lotion, emulsion lotion, varnish, poultice, and spray. It is done.

Ointment

An ointment can be produced by using a method for producing an ordinary ointment. For example, the active ingredient and the base can be heated and stirred, dispersed by heating, and then cooled to room temperature with stirring.

Cream

Creams can usually be produced by using a method for producing creams. For example, first, the base can be produced under heating and stirring, and the active ingredient itself or a solution containing it can be added under heating and stirring, and the resulting emulsion can be cooled to room temperature.

Lotion preparation

Lotions can usually be produced by using a method for producing a lotion, such as an oily base or a mixture of a heated and melted oily base and an aqueous base, the active ingredient itself or this. Can be prepared by adding a solution containing, with heating and stirring, then adding an aqueous base, and cooling the resulting liquid to room temperature.

Patch

The patch can usually be manufactured by using the method of manufacturing the patch. For example, an additive is added to a mixed base of a heated and melted oily base and an aqueous base while stirring. The active ingredient itself or a solution containing it is added under heating and stirring, and the resulting plaster is spread on a non-woven fabric and cut into an appropriate size, or heated and melted oil base The active ingredient itself or a solution containing it is added to the mixed base under heating and stirring, and then this is added to the heated and melted mixture of the synthetic resin while stirring, and the resulting plaster is added to the nonwoven fabric. Alternatively, it can be produced by spreading it on a woven fabric and cutting it into an appropriate size.

Support When the support is used, it is appropriately selected depending on the dosage form, but the active ingredient is preferably impermeable or hardly permeable and flexible, for example, cellulose acetate, ethyl cellulose, polyethylene, polypropylene.

, Polyvinyl chloride beer, Pinyl acetate-vinyl chloride copolymer, Ethylene monovinyl acetate copolymer, Ethylene monoacetate-carbon monoxide copolymer, Ethylene monobutyl acrylate-carbon monoxide copolymer, Polyvinylidene chloride, Polyurethane, Nylon Adhesives such as resin films such as polyethylene terephthalate and boribylene terephthalate, aluminum sheets, woven fabrics, non-woven fabrics, and laminated sheets thereof

When using an adhesive, any pharmaceutically acceptable one can be used, and conventionally known ones can be used. For example, acrylic adhesive, rubber adhesive, silicone adhesive, urethane adhesive An acrylic pressure-sensitive adhesive or a rubber-based pressure-sensitive adhesive is preferably used. Further, when spreading on the above-mentioned support, any properties such as a solvent-based, emulsion-based thermoplastic, and the like can be used as the properties of the pressure-sensitive adhesive.

Furthermore, if necessary, inorganic fillers such as kaolin, bentonite and titanium oxide, viscosity modifiers, anti-aging agents, pH adjusters, humectants such as glycerin and propylendalicol, buffering agents, preservatives, fragrances Etc. may be added.

Gel agent

Gels can usually be produced by using a method for producing a gel. For example, after a gel base is uniformly dissolved, an active ingredient is added, heated, dissolved, dispersed, etc. Any of the dosage forms can be produced by a normal manufacturing method. The use form is also arbitrary, for example, lotion, cream, emulsion, lotion, pack, ointment, mousse, and soap, foundation, eye shadow, blotch, lip cream, lip balm, Makeup cosmetics such as mascara, lipstick, body makeup products, hair rinses, shampoos, skin sunscreen creams or sun creams, dermatological ointments, bath preparations, etc. Alternatively, it can be used in any form as long as it is used in the dermatological field.

The method for producing the skin barrier function improving composition of the present invention is not particularly limited, and can be produced by a conventionally known method.

The skin barrier dysfunction-improving agent of the present invention is used as an external preparation for skin, and the composition as described above is transdermally administered to the skin of the subject or the entire skin of the body. In this case, the blending amount of the zinc hyaluronate complex (associate) is preferably 0.001 to 5% as a dry weight in the total amount of the external preparation, and particularly preferably 0.01 to 3%. Below this range, it is difficult to sufficiently exert the effect of suppressing epidermal moisture transpiration, that is, the effect of improving skin barrier dysfunction, and if it exceeds this range, stickiness and problems of lowering the feeling of use may occur.

The application amount of the composition for improving skin barrier function of the present invention is not particularly limited depending on the concentration and the state of the application site, but it is usually 1 to several times a day, about 0.01 to 10 g / l times. It is preferable to apply.

Effect confirmation experiment

Skin barrier function improvement effect test

In the present invention, the skin barrier function improving effect can be evaluated by various methods, for example, it is destroyed by tape stripping on the skin of a mammal (eg, rabbit, mouse, rattle, rabbit, etc.). Through the process of recovery of the damaged skin Paria ability to its original state It can be measured quantitatively or qualitatively by evaluating the amount of transpiration (TEWL) as an index. Such measurement can be performed, for example, as follows.

Skin moisturizing effect test

In the present invention, the skin moisturizing effect can be evaluated by various methods. For example, a skin injury model with erythema of the degree of erythema induced by SLS (sodium lauryl sulfate) on the skin of a mammal (eg, guinea pig). It can be measured by observing the effect of zinc hyaluronate complex (aggregate) on the stratum corneum moisture content. Such measurement can be performed, for example, as follows.

Example .

Next, the present invention will be described more specifically with reference to examples.

Example 1. Effect of zinc hyaluronate complex (aggregate) on TEWL in model skin barrier dysfunction in the evening due to aseton defatting (dose-response study)

Examination of 0.125%, 0.25%, 0.5%, and 1% zinc hyaluronate complex (associate) gel effect and dose response to TE WL in a model of skin barrier dysfunction in buyu caused by acetone degreasing did.

On the next day after hair removal, 6 sites were set symmetrically from the center of the back of the evening, and a total of 12 sites with a diameter of 3 cm were set. Attach a stainless steel cylinder with an inner diameter of 1.8 cm to the center, inject 5 mL of acetone for degreasing, collect all after 5 minutes, and then inject 5 mL of water for injection to remove natural moisturizing factor. After 3 minutes, the entire amount was collected and a skin barrier dysfunction model was prepared. The amount of coating per spot is about 3 cm in diameter with a zinc hyaluronate complex (aggregate) gel (0.125%, 0.25%, 0.5% and 1%) or gel base. 0.002 mL each was applied openly twice a day, without application, and TEWL was measured before model production, 4, 24, '48, 72 and 96 hours after production. ' 0.25% zinc hyaluronate complex (aggregate) after 4 hours on gel, 0.5% zinc hyaluronate complex (aggregate) after 1, 24, 48 and 72 hours on gel, 1% zinc hyaluronate complex In the body (aggregate) gel, significant improvement of TEWL was observed at all measurement points (Fig. 1). The area under the TEWL-time curve (hereinafter referred to as AUC) is a significant improvement in TEWL at a concentration of 0.25% or more of the zinc hyaluronate complex (aggregate) gel compared to the gel base. As shown in Fig. 2, the propensity test confirmed the improvement effect according to the concentration.

Example 2. Effect of zinc hyaluronate complex (aggregate) on TEWL in model of skin barrier dysfunction in buyu caused by acetone degreasing (comparison test with other agents)

In order to confirm the strength of action of zinc hyaluronate complex (aggregate) on TE WL in the model of skin barrier dysfunction of buyu caused by acetone degreasing, we used 0.3% heparin analog ointment and a common moisturizer. A comparative study of the efficacy of 20% urea ointment and 1% zinc hyaluronate complex (aggregate) gel was conducted.

On the next day after hair removal, 6 sites were set symmetrically from the center of the back of the evening, and a total of 12 sites with a diameter of 3 cm were set. Attach a stainless steel cylinder with an inner diameter of 1.8 cm to the center, inject 5 mL of acetone for degreasing, collect all after 5 minutes, and then inject 5 mL of water for injection to remove natural moisturizing factor. After 3 minutes, the entire amount was collected and a skin barrier dysfunction model was prepared. The application amount per spot is a gel base, hydrophilic ointment base, 1% zinc hyaluronate complex (associate) gel, 0.3% heparin analog ointment or 20% for a circle with a diameter of 3 cm. Urea ointment was applied openly at 0. 15 mL each, twice a day, without application, and TEWL was measured before model preparation, 4, 24, 48, 72 and 96 hours after preparation.

1% zinc hyaluronate complex (aggregate) The gels are 24, 48, 72 and 9 After 6 hours, a significant improvement in TEWL was observed compared to 0.3% heparin-like ointment and 20% urea ointment (Fig. 3). TEWL's AUC also showed a significant improvement compared to 0.3% heparin-like ointment and 20% urea ointment, so 1% zinc hyaluronate complex (combination) gel It was thought that the improvement effect of TEWL was stronger (Fig. 4).

¾Example 3. Effect of zinc hyaluronate complex (aggregate) on TEWL in model of skin barrier dysfunction in the evening due to aceton degreasing

(Comparison test of zinc hyaluronate complex (associate) with sodium hyaluronate, zinc chloride and mixtures)

Regarding the action of 1% zinc hyaluronate complex (aggregate) gel on TE WL in the model of skin barrier dysfunction of buyu caused by acetone degreasing, the following were obtained: 0.176% sodium hyaluronate gel, 0.166% zinc chloride gel and Compared with these mixed gels (mixed gel of sodium hyaluronate and zinc chloride with 0.09% sodium chloride added so that sodium hyaluronate and zinc chloride do not form a complex), the effects of hyaluronic acid were compared. We investigated the significance of zinc complex (aggregate) as a complex.

On the next day after hair removal, 7 sites were set symmetrically from the center of the back of the evening, and a total of 14 sites with a diameter of 3 cm was set. Attach a stainless steel cylinder with an inner diameter of 1.8 cm to the center, inject 5 mL of acetone for degreasing, collect all after 5 minutes, and then inject 5 mL of water for injection to remove natural moisturizing factor. After 3 minutes, the entire amount was collected and a skin barrier dysfunction model was prepared. The application amount per spot is 1% zinc hyaluronate complex (aggregate) gel, 3 .6% sodium hyaluronate gel, 0.166% zinc chloride gel, sodium hyaluronate-salt Zinc mixture gel, gel base or mixture gel base (hereinafter referred to as “NaCl-containing gel base”) is applied in an amount of 0.02 mL, open twice a day, without application, before making the model. TEWL was measured after 4, 24, 48, 72 and 96 hours. The 1% zinc hyaluronate complex (aggregate) gel showed a significant improvement in TEWL at all measurement points after application compared to the gel base. A mixed gel of sodium hyaluronate zinc monochloride also showed a significant TEWL improvement effect at 48 and 72 hours after application compared to the NaCl-containing gel base, but the effect of sodium zinc hyaluronate was The 1% zinc hyaluronate complex (aggregate) gel was stronger than the mixture gel (Figures 5 and 6).

From these results, 1% zinc hyaluronate complex (aggregate) gel was observed to improve TEWL in the model of skin barrier dysfunction in Bubayu, and the improvement effect of zinc hyaluronate complex (aggregate) The existence was presumed to be important.

Example 4. Effect of zinc hyaluronate complex (aggregate) on a model of skin barrier dysfunction associated with erythema-like dermatitis induced by SLS (sodium lauryl sulfate) in guinea pigs (dose-response study)

Improvement of TEWL of 0.125%, 0.25%, 0.5%, 0.75% and 1% zinc hyaluronate complex (aggregate) gel in a model of skin barrier dysfunction with SLS-induced erythema-like dermatitis using guinea pigs The effects and dose response were examined.

On the next day after hair removal, 50 L of 2% SLS aqueous solution was dropped on the adhesive bandage on the back of Std: Hartley guinea pig and applied to the right dorsal side for 12 hours to prepare a skin barrier dysfunction model. Zinc hyaluronate complex (aggregate) 2cm ² per site Gel (0.125%, 0.25%, 0.5% and 1%) or gel base each 0.02mL, apply twice a day, uncoated TEWL was measured every day before and 6 days after application.

0.75% zinc hyaluronate complex (aggregate) The gel is 2 days, 1% zinc hyaluronate complex (aggregate) The gel is 2 days and 4 days A significant improvement of TEWL was observed (Fig. 7). In addition, when TEWL was measured over time, the 0.75% and 1% zinc hyaluronate complex (aggregate) gels showed a significant improvement in TEWL compared to the gel base. The test showed an improvement effect depending on the concentration (Fig. 8 Example 5. Zinc hyaluronate complex for skin barrier dysfunction model with erythema-like dermatitis induced by guinea pig SLS (sodium lauryl sulfate) (Association) action (comparison test with other drugs)

To evaluate the strength of TEWL-improving effect of zinc hyaluronate complex (aggregate) on skin barrier dysfunction model with dermatitis of erythema level induced by SLS using guinea pigs, 0.5% and 1% hyaluronic acid Zinc complex (Aggregate) A comparative study was conducted between the gel and 0.3% heparin analog ointment and 20% urea ointment, a commonly used moisturizer.

The day after depilation, Std: 50 L of 2% SLS aqueous solution was dropped on the back of the patch 11 for Har 11 ey guinea pigs and applied to the right dorsal region for 12 hours to create a skin barrier dysfunction model. did. 2cm ² of hyaluronate complex (aggregate) gel (0.5% and 1%), 0.3% heparin analog ointment, 20% urea ointment, gel base or hydrophilic ointment base 0.02 m, open application twice a day, no application, TEWL was measured on each day before drug application and 6 days after application.

0.5% and 1% zinc hyaluronate complex (associate) Gel is 0.3% to 3% heparin analog ointment on days 3-6, 0.5% zinc hyaluronate complex (associate) On day 5, the 1% zinc hyaluronate complex (aggregate) gel showed a significant improvement in TEWL compared to 20% urea ointment on days 3-6 (Figure 9). In addition, from the cumulative total of 6 days of TEWL measured over time, 0.5% and 1% zinc hyaluronate complex (aggregate) gel was obtained from 0.3% heparin analog's ointment and 20% urea ointment. Bara Kai The good action was considered excellent (Fig. 10).

Example 6. Effect of zinc hyaluronate complex (associate) on model of skin barrier dysfunction with erythema-like dermatitis induced by SLS (sodium lauryl sulfate) in guinea pigs (zinc hyaluronate complex (associate) ) And sodium hyaluronate, zinc chloride and mixtures of these)

Regarding the action of 1% zinc hyaluronate complex (aggregate) gel on TEWL in a model of skin barrier dysfunction with erythema-like dermatitis induced by SLS using guinea pigs We compared the effect with a mixture gel of 166% zinc chloride gel and sodium hyaluronate zinc monochloride, and investigated the significance of zinc hyaluronate complex (aggregate) as a complex.

On the next day after hair removal, 50 L of 2% SLS aqueous solution was dropped on the patch bandage on the back of Std: Hartley guinea pigs and applied to the right back for 12 hours to create a skin barrier dysfunction model. did. 1 cm zinc hyaluronate complex (aggregate) gel at 2 cm ² per site, 0.176% sodium hyaluronate gel, 0.166% zinc chloride gel, sodium hyaluronate zinc monochloride gel, gel base The drug or NaCl-containing gel base was applied in an open dose of 0.02 mL, twice a day, without application, and TEWL was measured on each day before and 6 days after application.

The 1% zinc hyaluronate complex (aggregate) gel showed a significant improvement in TEWL on days 2, 4 and 5 compared to the gel base, and the effects of sodium hyaluronate gel and zinc chloride gel at the equivalent concentrations Exceeded. In addition, a mixed gel of sodium hyaluronate zinc monochloride also showed a significant TEWL improvement effect on day 3 compared to the NaCl-containing gel base, but the effect was 1% zinc hyaluronate complex (association). Material) Gel was stronger (Figures 1 and 12) From these results, in the guinea pig skin barrier dysfunction model, 1% zinc hyaluronate complex (aggregate) gel was found to have an effect of improving TEWL. Was presumed to be important.

Example 7. Effects of zinc hyaluronate complex (aggregate) on stratum corneum water content in a model of dermatosis associated with erythema-like dermatitis induced by SLS (sodium lauryl sulfate) in guinea pigs (dose-response study_ )

0.25%, 0.25%, 0.5%, 0.75%, and 1% zinc hyaluronate complex (aggregate) in stratum corneum moisture in LS-induced dermatosis-induced dermatitis model using guinea pigs We examined the dose response in increasing dose.

On the next day after hair removal, 50 L of 2% SLS aqueous solution was dropped on the back of the patchette wings on the back of Std: Hartley guinea pigs and applied to the right dorsal side for 12 hours to prepare a skin disorder model. Zinc hyaluronate double per 2 cm ² 1 place. Coalesce (association of) gel (0.125%, 0.25%, 0.5% and 1%) or gel base each 0.02 mL, open applied twice daily, no Coating was provided, and the stratum corneum moisture content was measured on each day before and 6 days after the drug application.

0.75% zinc hyaluronate complex (aggregate) The gel is on the 3rd day, 1% zinc hyaluronate complex (aggregate) The gel is on the 3rd, 4th, 5th and 6th days. Increased water content was observed (p 0.01, p 0.01, p 0.01, p 0.05, and p 0.01, respectively). In the trend test, an improvement effect corresponding to the concentration was observed at each time point (p <0.01 for all) (Fig. 13).

Example 8. Effect of zinc hyaluronate complex (aggregate) on keratinous water content in dermatosis model with erythema-like dermatitis induced by SLS (sodium lauryl sulfate) in guinea pigs (Comparative test of lead complex (aggregate) with sodium hyaluronate, zinc chloride and mixtures thereof).

1% Zinc Hyaluronate Complex (Association) on the skin damage model with erythema-like dermatitis induced by SLS using guinea pigs About the increase in keratin water content of gel, 0.976% sodium hyaluronate, 0.166% chloride The effect of the zinc gel and sodium hyaluronate mixed monobasic monochloride was compared and the significance of the zinc hyaluronate complex (aggregate) as a complex was investigated.

On the next day after hair removal, 50 L of 2% SLS aqueous solution was dropped on the patch bandage on the back of the Std: HarUey guinea pig and applied to the right dorsal side for 12 hours to prepare a skin injury model. 2cm ² per site 1% zinc hyaluronate complex (aggregate) gel, 0.976% sodium hyaluronate gel, 0.1 66% zinc chloride gel, sodium hyaluronate zinc monochloride mixture gel, gel base or NaCl 0.02 mL each of the gel base was applied openly twice a day, without application, and the stratum corneum water content was measured on each day before and 6 days after application.

1% zinc hyaluronate complex (aggregate) The gel showed a significant increase in stratum corneum water content at all measurement points after the second day after the start of application compared to the gel base (p 0.01). It exceeds the effect of 0.976% NaHA gel and 0.166% ZnCl ₂ gel (Figure 14). In addition, the mixture gel also showed a significant increase (p <0.01 on the 2nd to 5th days, p <0.05 on the 6th day) compared to the NaCl-containing gel base at all measurement points after the 2nd day after the start of application. However, the effect was stronger in the 1% zinc hyaluronate complex (aggregate) gel (Fig. 15).

Example 9. Effect of zinc hyaluronate complex (associate) on stratum corneum water content in a model of skin barrier dysfunction with SLS-induced erythema-induced dermatitis in guinea pigs (comparison test with other agents) In order to evaluate the strength of the increase in stratum corneum water content of the zinc hyaluronate complex (aggregate) on the skin damage model with erythema-like dermatitis induced by SLS using guinea pigs, 0.5% and 1% hyaluron Oxide complex (aggregate) A comparative study was conducted between the gel and 0.3% heparin-like substance ointment and 20% urea ointment, a common moisturizer.

On the next day of hair, 50 iL of 2% SLS aqueous solution was dropped on the patch bandage on the back of Std: Hartley guinea pigs and applied to the right dorsal side for 12 hours to prepare a skin barrier dysfunction model. 2cm ² of hyaluronate complex (aggregate) gel (0.5% and 1%), 0.3% heparin analog ointment, 20% urea ointment, gel base or hydrophilic ointment base 0.02 mL, applied twice a day, without application, and the stratum corneum moisture content was measured on each day before and 6 days after application.

Compared to the gel base, 0.5% zinc hyaluronate complex (aggregate) The gel was applied on the 2nd and 6th day of application (ρ <0 · 05, respectively), 1% zinc hyaluronate complex (aggregate) Showed a significant increase in stratum corneum water content on days 2, 3, 4, 5 and 6 (roughly 0.01 on days 2, 4, 5, and 6 and 0.05 on day 3). (Figure 16). 0.3% heparin-like substance Compared to ointment, 0.5% zinc hyaluronate complex (aggregate) gel is 6th day (crack 0.01), 1% zinc hyaluronate complex (aggregate) gel is 4-6 days There was a significant increase in eyes (rho 0.05 on day 4, rho 0.01 on days 5 and 6). Compared with 20% urea ointment, 0.5% zinc hyaluronate complex (associate) gel was applied on the 4th day (ρ 0.05), 1% zinc hyaluronate complex (associate) gel was 2-6 A significant increase (.rho.0.01 each) was observed on the day (Fig. 17).

Formulation examples

(1) Preparation method

Zinc hyaluronate complex and hydrophobized hydroxypro in the following formulation All of the ingredients except for pyrmethylcellulose were dissolved in about 80 parts by weight of purified water. To this solution, the zinc hyaluronate complex was added in small portions and dissolved, and then heated to about 70 ° C, and hydrophobized hydroxypropyl methylcellulose was added in small portions and dispersed. The suspension was made up to 100 parts by weight with purified water and then cooled to room temperature to form a gel. This gel was filled into an aluminum laminate tube and sealed.

(2)

Zinc hyaluronate complex 0.1 2 5 to 1 Hydrophobized hydroxypropyl methylcellulose 9 0 L

Ten

Concentrated glycerin 1 0.0 parts Methyl paraoxybenzoate 0.1 5 parts by weight Propyl paraoxybenzoate 0.02 parts by weight Purified water _ Suitable amount

Total 1 0 0. 0

Formulation comparison example

(1) Preparation method

All of the formulation components except for the hydrophobized hydroxypropylmethylcellulose in the following formulation were dissolved in about 80 parts by weight of purified water. This solution was heated to about 70 ° C., and hydrophobized hydroxypropylmethylcellulose was added in small portions and dispersed. The suspension was made up to 100 parts by weight with purified water and then cooled to room temperature to form a gel. The gel was filled into an aluminum laminate tube and sealed.

(2) Prescription

Hydrophobized hydroxypropyl methylcellulose 90 L

1. 0 parts by weight Concentrated glycerin '1 0.0 parts by weight Methyl paraoxybenzoate 0.1 5 parts by weight Propyl paraoxybenzoate 0.02 parts by weight Purified water

Total 0 0. 0 parts by weight

Claims

The scope of the claims

I. A skin condition improving agent comprising a zinc hyaluronate complex (aggregate).

2. The skin condition improving agent according to claim 1, wherein the improvement of the skin condition is improvement of skin barrier function, enhancement of moisturizing action, improvement of sebum deficiency condition, or improvement of xeroderma.

3. The skin condition-improving agent according to claim 1 or 2, wherein the zinc hyaluronate complex (associate) has an average molecular weight of about lOOkD to about 2,000 kD.

4. The skin condition improving agent according to claim 3, wherein the zinc hyaluronate complex (aggregate) has an average molecular weight of about 400 kD to 1,200 kD.

5. The skin condition improving agent according to claim 4, wherein the zinc hyaluronate complex (aggregate) has an average molecular weight of about 1, OOOkD.

6. The skin condition improving agent according to any one of claims 1 to 5, wherein a weight ratio of hyaluronic acid to zinc is 5:;! To 20: 1.

7. The skin condition improving agent according to claim 6, wherein the weight ratio of hyaluronic acid and zinc is about 10: 1.

8. Use of zinc hyaluronate complex (aggregate) for the manufacture of skin condition improvers.

9. The use according to claim 8, wherein the improvement of the skin condition is improvement of skin barrier function, enhancement of moisture retention, improvement of sebum deficiency, or improvement of xeroderma.

10. Use according to claim 8 or 9, wherein the zinc hyaluronate complex (associate) has an average molecular weight of about lOOkD to about 2,0 OOkD.

II. Use according to claim 10, wherein the zinc hyaluronate complex (associate) has an average molecular weight of about 400 kD to 1,200 kD.

1 2. Use according to claim 11, wherein the zinc hyaluronate complex (associate) has an average molecular weight of about l. OOOkD.

1 3. Use according to any one of claims 8 to 12, wherein the weight ratio of hyaluronic acid to zinc is 5: 1 to 20: 1.

1 4. Use according to claim 13, wherein the weight ratio of hyaluronic acid to zinc is about 10: 1.

1 5. A method for improving skin condition, characterized by administering zinc hyaluronate complex (aggregate) to a patient in need of skin condition improvement

1 6. The method according to claim 15, wherein the improvement of the skin condition is improvement of skin barrier function, enhancement of moisturizing action, improvement of sebum deficiency condition, or improvement of xeroderma.

17. The method according to claim 15 or 16, wherein the zinc hyaluronate complex (associate) has an average molecular weight of about lOOkD to about 2,0 OOkD.

18. The method according to claim 17, wherein the zinc hyaluronate complex (associate) has an average molecular weight of about 400 kD to 1,200 kD.

19. The method according to claim 18, wherein the zinc hyaluronate complex (associate) has a molecular weight of about 1, 000 kD.

20. The method according to any one of claims 15 to 19, wherein the weight ratio of hyaluronic acid to zinc is 5: 1 to 20: 1.

2 1. The method of claim 20, wherein the weight ratio of hyaluronic acid to zinc is about 10: 1.