JP2003246737A - External preparation for skin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an external preparation for skin which is used for maintaining the skin in good conditions or for exerting a sufficient effect in treating skin diseases. <P>SOLUTION: The external preparation for the skin contains sodium cromoglycate and a monoester of a polyhydric alcohol and salicylic acid in a base. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external composition for skin which keeps the skin healthy and exerts a sufficient effect in treating skin diseases.

[0002]

2. Description of the Related Art Sodium cromoglycate (1,3-bis (2-
Carboxychromone-5-yloxy) -2-hydroxypropane sodium salt) is known as a substance that suppresses the release of chemical mediators from mast cells during type I allergic reactions. It is used for treating allergic diseases such as allergic asthma by administering the preparation by inhalation.

Further, JP-A-52-44242 discloses that sodium cromoglycate is locally administered to skin or eye tissues and used for the treatment of chronic skin diseases and eye diseases involving allergic or immune reactions. It is disclosed. Further, JP-A-11-335281 and JP-A-11-335282 disclose that an external preparation containing sodium cromoglycate is effective for treating skin diseases such as dry skin.

However, the therapeutic effect on skin diseases by the external preparation containing sodium cromoglycate was not always sufficient.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a composition for external application to the skin, which is used for keeping the skin healthy or exerting a sufficient effect in treating a skin disease. .

[0006]

Means for Solving the Problems As a result of intensive studies on the pharmacological action of sodium cromoglycate, the present inventors have found that by using sodium cromoglycate in combination with monoesters of polyhydric alcohol and salicylic acid, The present inventors have found that the effect of sodium for keeping skin healthy or treating skin diseases is remarkably improved, and have completed the present invention.

That is, the external composition for skin according to claim 1 is characterized in that sodium cromoglycate and a monoester of polyhydric alcohol and salicylic acid are contained in the base.

The external composition for skin according to claim 2 is the external composition for skin according to claim 1, characterized in that the monoester of the polyhydric alcohol and salicylic acid is glycol salicylate.

The external composition for skin according to claim 3 has a content of the monoester of the polyhydric alcohol and salicylic acid.
The external composition for skin according to claim 1 or 2, wherein the composition is 1 to 20% by weight.

The external composition for skin according to claim 4 is N-acyl sarcosine or a salt thereof, a higher fatty acid ester of a higher fatty acid having 10 to 18 carbon atoms and an alcohol having 1 to 20 carbon atoms, and a higher fatty acid having 2 to 10 carbon atoms. Dicarboxylic acid or salt thereof, hydroxycarboxylic acid ester of hydroxycarboxylic acid having 3 to 6 carbon atoms and alcohol having 1 to 20 carbon atoms, fatty acid ethanolamide, glycerin, propylene glycol, polyethylene glycol, urea, glycyrrhizinic acid, squalane and muco 4. The external composition for skin according to claim 1, wherein at least one transdermal absorption enhancer selected from the group consisting of polysaccharides is further contained in the base.

The external composition for skin according to claim 5 is at least one percutaneous absorption enhancer selected from the group consisting of glycerin, propylene glycol, urea, squalane and mucopolysaccharide. The external composition for skin according to item 4.

The external composition for skin according to claim 6 is characterized in that the base is a water-soluble base.
The composition for external use for skin according to 3, 4, or 5.

The external composition for skin according to claim 7 has a pH of 2
It is characterized by being ~ 7, Claims 1, 2, 3, 4, 5
Or the external composition for skin according to item 6.

The external composition for skin according to claim 8 has a pH of 4
~ 5, Claims 1, 2, 3, 4,
The external composition for skin according to 5 or 6.

The invention according to claim 9 is based on claim 1, 2,
A cosmetic or pharmaceutical product, which contains the external composition for skin according to 3, 4, 5, 6, 7 or 8.

The present invention will be described in detail below. The external composition for skin of the present invention contains sodium cromoglycate as an active ingredient and a monoester of polyhydric alcohol and salicylic acid in a base. It is considered that a high therapeutic effect can be obtained by combining sodium cromoglycate with a monoester of polyhydric alcohol and salicylic acid.

When the content of sodium cromoglycate in the external composition for skin of the present invention is small, the effect is not sufficient, and when it is too large, the effect does not remarkably increase according to the content, and the formulation Since the above problem also occurs, the lower limit is preferably 0.1% by weight, more preferably 0.
It is 3% by weight, particularly preferably 0.5% by weight, and its upper limit is preferably 50% by weight, more preferably 30% by weight, particularly preferably 10% by weight.

The above-mentioned monoester of polyhydric alcohol and salicylic acid is an ester which is a reaction product of one molecule of polyhydric alcohol and one molecule of salicylic acid, and examples thereof include glycol salicylate (ethylene glycol salicylate), propylene glycol salicylate and glycerin. Examples thereof include salicylic acid monoester, and glycol salicylate is particularly preferable in the present invention.

When the content of the monoester of polyhydric alcohol and salicylic acid in the external composition for skin of the present invention decreases, the effect of promoting percutaneous absorption becomes insufficient, and even if it is too large, the effect remarkably depends on the content. It will not be high, and
Since there is also a problem in dosage form, the lower limit thereof is preferably 0.1% by weight, more preferably 0.5% by weight, particularly preferably 1% by weight, and the upper limit thereof is preferably 50% by weight, more preferably 30% by weight, particularly preferably 20% by weight
Is.

In the external composition for skin of the present invention, it is preferable that the base further contains a percutaneous absorption enhancer.

The above-mentioned percutaneous absorption enhancer is N-acyl sarcosine or a salt thereof, a higher fatty acid having 10 to 18 carbon atoms and 1 to 2 carbon atoms.
Higher fatty acid ester with 0 alcohol, dicarboxylic acid having 2 to 10 carbon atoms or salt thereof, hydroxycarboxylic acid ester of hydroxycarboxylic acid having 3 to 6 carbon atoms and alcohol having 1 to 20 carbon atoms, fatty acid ethanolamide, glycerin , Propylene glycol, polyethylene glycol,
At least one selected from the group consisting of urea, glycyrrhizinic acid, squalane and mucopolysaccharide is suitable.

Examples of the mucopolysaccharides include hyaluronic acid, chondroitin, chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, keratan sulfate, and pharmacologically acceptable salts thereof.

The above-mentioned N-acyl sarcosine includes, for example, N-lauroyl sarcosine, N-oleoyl sarcosine, N-palmitoyl sarcosine, coconut oil fatty acid sarcosine, and the salts thereof include, for example, the above-mentioned N-acyl sarcosine. Examples thereof include sarcosine sodium salt, potassium salt, magnesium salt, calcium salt, and aluminum salt.

The higher fatty acid ester is a reaction product of a higher fatty acid and an alcohol. If the carbon number of the higher fatty acid becomes smaller, the higher fatty acid ester of the product will easily volatilize, and if it becomes larger, the transdermal absorption effect will decrease.
It is preferably 10 to 18, and the carbon number of the alcohol is preferably 1 to 20 because the transdermal absorption effect decreases as it increases.

The higher fatty acid having 10 to 18 carbon atoms includes
Saturated aliphatic monocarboxylic acids such as capric acid, lauric acid, myristic acid, palmitic acid, stearic acid;
Examples thereof include unsaturated aliphatic carboxylic acids such as palmitoleic acid, oleic acid, vaccenic acid, linoleic acid and linolenic acid; and saturated aliphatic dicarboxylic acids such as sebacic acid.

As the alcohol having 1 to 20 carbon atoms,
For example, methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, tertiary butyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, capryl alcohol, nonyl alcohol, decyl alcohol, lauryl alcohol, myristyl Examples thereof include alcohols, aliphatic saturated alcohols such as palmityl alcohol and stearyl alcohol.

Examples of the higher fatty acid ester include isopropyl myristate, isopropyl palmitate, isopropyl laurate, isopropyl stearate and the like.

The carbon number of the above dicarboxylic acid or its salt is
If it is too small or too large, the transdermal absorption effect will decrease.
It is preferably from 2 to 10.

Examples of the dicarboxylic acid having 2 to 10 carbon atoms include saturated aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid and suberic acid; fumaric acid and maleic acid. Unsaturated aliphatic dicarboxylic acids such as; aromatic dicarboxylic acids such as phthalic acid, isophthalic acid, and terephthalic acid, and the like. Examples of salts thereof include sodium salts, calcium salts, and aluminum salts of the above dicarboxylic acids. To be

The hydroxycarboxylic acid ester is a reaction product of a hydroxycarboxylic acid and an alcohol. When the carbon number of the hydroxycarboxylic acid is small, the hydroxycarboxylic acid ester of the product is liable to volatilize, and when it is large, the transdermal absorption effect is deteriorated.
The carbon number of the alcohol is preferably 1 to 20 because the transdermal absorption effect decreases as the alcohol increases.

Examples of the hydroxycarboxylic acid having 3 to 6 carbon atoms include monocarboxylic acids such as lactic acid and glycerin, and dicarboxylic acids such as malic acid and tartaric acid.

As the alcohol having 1 to 20 carbon atoms,
The same thing as what is used for the reaction of the above-mentioned higher fatty acid ester is mentioned.

Examples of the hydroxycarboxylic acid ester include myristyl lactate and cetyl lactate.

Examples of the fatty acid ethanolamide include lauric acid monoethanolamide, lauric acid diethanolamide, lauroyl monoethanolamide,
Palmitic acid monoethanolamide, palmitic acid diethanolamide, myristic acid monoethanolamide,
Myristic acid diethanolamide, lauric acid / myristic acid monoethanolamide, coconut oil fatty acid monoethanolamide, coconut oil fatty acid diethanolamide, polyoxyethylene-added lauroyl monoethanolamide, polyoxyethylene-added coconut oil fatty acid monoethanolamide, etc. .

When the amount of the above-mentioned percutaneous absorption enhancer in the external composition for skin of the present invention is small, the percutaneous absorption promoting effect is low, and when it is too large, skin irritation is exhibited or fluidity is too high. Depending on the base, it may be difficult to maintain the dosage form, so the total amount of sodium cromoglycate and base is 100
With respect to parts by weight, the lower limit is preferably 0.1 parts by weight, more preferably 10 parts by weight, and the upper limit is preferably 20,000 parts by weight, more preferably 10,000 parts by weight.

The base used in the present invention may be any pharmaceutically acceptable base, and conventionally known bases such as ointments, liniments and lotions can be used. For example, Sodium alginate, propylene glycol alginate, gelatin, corn starch, tragacanth gum, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, dextrin, carboxymethyl starch, polyvinyl alcohol, sodium polyacrylate, methoxyethylene-maleic anhydride copolymer, polyvinyl ether, polyvinyl. Polymers such as pyrrolidone, beeswax,
Olive oil, cacao oil, sesame oil, soybean oil, camellia oil,
Fats and oils such as peanut oil, beef oil, pork oil, lanolin; white petrolatum; paraffin; gelled hydrocarbon (for example, trade name Plastibase, manufactured by Bristol-Myers Squibb); higher fatty acids such as stearic acid; cetyl alcohol, stearyl Higher alcohols such as alcohols; polyhydric alcohols such as glycerin, propylene glycol and ethylene glycol; polyethylene glycols; surfactants; water and the like.

Examples of the above surfactants include lecithin derivatives, propylene glycol fatty acid esters, glycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene sorbit. Fatty acid ester,
Polyoxyethylene alkylphenyl formaldehyde condensate, polyoxyethylene castor oil, hydrogenated castor oil,
Polyoxyethylene sterol / hydrogenated sterol,
Polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene lanolin / lanolin alcohol / beeswax derivative, polyoxyethylene alkylamine / fatty acid amide, polyoxyethylene alkyl ether phosphate / phosphoric acid Examples thereof include salts and polymeric emulsifiers, but are not limited to these.

Particularly, as a base material suitable for the present invention,
Water-soluble bases can be mentioned, and specific examples of the constituent components include:
Examples thereof include water, glycerin, propylene glycol, or a mixture thereof, or a water-soluble gel obtained by adding a polyacrylic acid salt to these substances.

In addition to the above, the base used in the present invention also includes a pressure-sensitive adhesive that has been conventionally used in plasters and tapes. The pressure-sensitive adhesive may be any pharmaceutically acceptable one, and any conventionally known one can be used,
For example, acrylic pressure sensitive adhesive, rubber pressure sensitive adhesive, silicon pressure sensitive adhesive, urethane pressure sensitive adhesive and the like can be mentioned, and acrylic pressure sensitive adhesive and rubber pressure sensitive adhesive are preferably used. As the property of the pressure-sensitive adhesive, any of solvent type, emulsion type, hot melt type and the like can be used.

Examples of the acrylic adhesive include, for example,
Examples of the adhesive include a polyalkyl (meth) acrylate mainly obtained by copolymerizing an alkyl (meth) acrylate, and a polyfunctional monomer copolymerizable with the alkyl (meth) acrylate or another vinyl monomer. It may be a polymer.

Examples of the alkyl (meth) acrylate include 2-ethylhexyl (meth) acrylate,
Dodecyl (meth) acrylate etc. are mentioned.

Examples of the polyfunctional monomer include
1,6-hexane glycol methacrylate, tetraethylene glycol diacrylate and the like are listed, and examples of the other vinyl monomer include N-vinyl-2-pyrrolidone, vinyl acetate and the like.

Examples of the rubber-based pressure-sensitive adhesive include pressure-sensitive adhesives mainly composed of natural rubber, styrene-isoprene-styrene block copolymer, styrene-olefin-styrene block copolymer, etc. Generally, rosin and hydrogenated A tackifier such as rosin, rosin ester, terpene resin, terpene phenol resin, petroleum resin, coumarone resin, coumarone-indene resin is added.

If necessary, various other medicinal components may be added to the external composition for skin of the present invention. The medicinal component is not particularly limited, and examples thereof include a steroidal anti-inflammatory agent, a nonsteroidal anti-inflammatory agent, an antiallergic agent, an antihistamine agent, a bactericidal disinfectant, an antibiotic, and an immunosuppressant.

In the external composition for skin of the present invention, if necessary, an inorganic filler such as kaolin, bentonite, zinc oxide or titanium oxide; a viscosity modifier, an antiaging agent, a pH modifier; a buffering agent; an antiseptic agent. Agents; fragrances and the like may be added.

If the pH of the external composition for skin of the present invention is too high, the stability of the monoester of polyhydric alcohol and salicylic acid of the external preparation will be poor, and if it is too low, irritation to the application site will occur and that of cromoglycic acid will be high. Since precipitation may occur, the lower limit is preferably pH 2, and more preferably p
It is H4, and the upper limit thereof is preferably pH 7, more preferably pH 5.

The method for preparing the external composition for skin of the present invention is not particularly limited, and examples thereof include a method of kneading the above sodium cromoglycate, a monoester of polyhydric alcohol and salicylic acid, and the like into the above base. .

The form of the external composition for skin of the present invention is not particularly limited. For example, the above-mentioned sodium cromoglycate is dissolved or mixed and dispersed in a base to prepare a cream-like, paste-like or jelly-like form. Those in the form of gel, emulsion or liquid (ointment, liniment,
Lotions, etc.); Dissolved or mixed dispersion of the above-mentioned sodium cromoglycate in a base material, spread on a support (Pap, etc.); Soluble or mixed sodium cromoglycate in an adhesive. Examples thereof include those in which the dispersed material is spread on the support (plaster agent, tape agent, etc.).

The above-mentioned support is appropriately selected according to its form, but it is preferably one which is impermeable or hardly permeable to the drug and is flexible, for example, cellulose acetate, ethyl cellulose,
Polyethylene, polyvinyl chloride, vinyl acetate-vinyl chloride copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl acetate-carbon monoxide copolymer, ethylene-butyl acrylate-carbon monoxide copolymer, polyvinylidene chloride , Polyurethane, nylon, resin film such as polyethylene terephthalate; aluminum sheet; woven fabric;
Examples include non-woven fabrics and laminated sheets thereof.

The uses of the external composition for skin of the present invention include:
For example, cosmetics, pharmaceuticals and the like can be mentioned. When it is used as a cosmetic, it is used as a lotion, emulsion, pack, etc. When used as a medicine, various skin diseases, for example, rough skin, rash, heat rash, sore, rash, diaper rash, atopic dermatitis, contact dermatitis,
Seborrheic dermatitis, Vidal lichen, coin-shaped eczema, housewife eczema, sun dermatitis, insect bite, pruritus cutaneus, prurigo, drug eruption, toxic eruption, psoriasis, psoriasis vulgaris, lichen planus, lichen planus , Lichen planus, erythema schizophrenia, gibber rosacea erythrocytosis, erythema,
Erythroderma, lupus erythematosus lupus, systemic lupus erythematosus, pemphigus, pemphigus vulgaris, Juling herpes dermatitis, alopecia areata, vitiligo vulgaris, sarcoidosis, cutaneous amyloidosis, keloid, hypertrophic scar, Wounds, pressure sores, skin ulcers,
It can be used to treat hair loss and the like.

The use amount of the external composition for skin of the present invention varies depending on the kind of the disease, the degree of the symptom, the size of the affected area, etc., but is preferably 0.1 to 10 g per day. Apply separately to the affected area.

(Examples) The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. (Examples 1 to 33 and Comparative Examples 1 to 16) A predetermined amount (% by weight) of each component shown in Tables 1 to 5 was mixed, and a gel agent, a cream agent or an ointment agent (hereinafter, these are collectively referred to as “test sample”). Also referred to as "agent." The following components were used as each component.

Sodium cromoglycate (manufactured by Fukuju Pharmaceutical Co., Ltd., hereinafter referred to as "DSCG"); glycol salicylate (trade name Saliment, manufactured by Yoshitomi Fine Chemical Co., Ltd., hereinafter "S")
G ”); Hydrophilic ointment (Maruishi Pharmaceutical Co., Ltd.); White petrolatum (Maruishi Pharmaceutical Co., Ltd.); Stearyl alcohol (Wako Pure Chemical Industries, Ltd.), Polyoxyethylene hydrogenated castor oil 60 (trade name HC)
O-60, manufactured by Nikko Chemicals, hereinafter referred to as "HCO-60");
Polyacrylic acid gel (Product name "Syntalene L, 3V" Sigm
a company, hereinafter "PA gel"); glycerin (Maruishi Pharmaceutical Co., Ltd.); propylene glycol (Maruishi Pharmaceutical company, hereafter "PG"); Alginic acid propylene glycol ester (Kibun Food Chemifa Co., hereafter, "APG ); Urea (Osakai Pharmaceutical Co., Ltd.); Sodium Hyaluronate (Asahi Kasei Co., Ltd., hereinafter "HA"); Squalane (Maruha Co., Ltd.); Salicylic Acid (Wako Pure Chemical Industries, Ltd., "SA"); Salicylic Acid Methyl (manufactured by Wako Pure Chemical Industries, Ltd., hereinafter “SM”); Lauric acid diethanolamide (manufactured by NOF Corporation, hereinafter “LD”); Triethanolamine (manufactured by Nippon Shokubai Co.); Methyl paraoxybenzoate (Yoshitomi Fine Chemical Co., Ltd.) Made, hereinafter referred to as "paraben")

"Vaseline and the like" in the base column of Tables 3 and 5 means white petrolatum: stearyl alcohol: HC
A mixture of O-60 = 6: 1: 1 (weight ratio) is shown.

(Test Example 1) Effect on primary skin irritation reaction induced by dinitrochlorobenzene: The back of 7-week-old Wistar male rats was shaved, and then
2,4-dinitrochlorobenzene (DNCB, Wako Pure Chemical Industries, Ltd.) 0.
20 μL of 8% (w / v) acetone (manufactured by Nacalai Tesque, Inc.) solution was added dropwise and dried. Next, 0.1 g of the above-mentioned test agent was placed on the polyethylene terephthalate surface of a circular polyethylene terephthalate / ethylene vinyl acetate laminated film having a radius of 1 cm, and the polyethylene terephthalate surface was attached so that this surface was in contact with the shaving part.

The film was peeled off 24 hours after application, and the erythema intensity at the same site was measured with a color difference meter (CR-200, manufactured by Minolta). As a control, instead of the above test agent, a control agent (DSCG in each test agent was replaced by each base component. However, the composition ratio of each base component is the base composition of the original test agent. The erythema intensity was measured in the same manner by using the ratio. Erythema intensity (Formula I
(Represented by (A)) and the erythema intensity of the test agent application site (represented by (B) in Formula I), the erythema inhibition rate was calculated by the following formula, and the results are shown in Tables 1 to 5. It was Suppression rate (%) = ((A)-(B)) / (A) × 100 Formula I

From the results of the inhibition rates shown in Tables 1 to 5, it can be seen that the external composition for skin of the present invention exerts a sufficient effect in treating skin inflammation.

(Test Example 2) Effect on type IV allergic reaction (dinitrochlorobenzene-induced skin contact hypersensitivity reaction)

The abdomen of a 5-week-old Wistar male rat was shaved, and then 20 μL of a 20% (w / v) acetone solution of 2,4-dinitrochlorobenzene was dropped and dried to be sensitized. Two weeks after the sensitization, the back of the rat was shaved, and then 20 μL of a 0.5% (w / v) acetone solution of 2,4-dinitrochlorobenzene was dropped and dried to induce a reaction. Next, add 0.1 g of the above test agent to the
1 cm circular polyethylene terephthalate / ethylene
It was placed on the polyethylene terephthalate surface of the vinyl acetate laminated film, and it was attached so that this surface was in contact with the back shaving part.

The film was peeled off 24 hours after application, and the erythema intensity at the same site was measured with a colorimeter. Also, as a control, instead of each of the above test agents, a control agent
The erythema intensity was measured in the same manner using (the DSCG in each test agent was replaced by each base ingredient, but the composition ratio of each base ingredient was the base composition ratio of the original test agent). . Erythema intensity of the control agent application site (represented by (A) in Formula I)
Also, the erythema inhibition rate was calculated by the following formula from the measurement results of the erythema intensity (represented by (B) in Formula I) of the test agent application site, and the results are shown in Tables 1 and 5. Suppression rate (%) = ((A)-(B)) / (A) × 100 Formula I

From the results of the erythema suppression rate shown in Tables 1 and 5, it is understood that the external composition of the present invention exerts a sufficient effect in treating skin inflammation associated with type IV allergy.

(Test Example 3) Effect on type I allergic reaction (48-hour homologous PCA reaction) (1) Preparation of rat anti-2,4-dinitrobenzenesulfonic acid-round swine extract (DNP-As) serum

The method of Tada and Okumura (Journal of Immu
nology, 106, 1002, 197) was used to prepare DNP-As. The extract of Ascaris suum was treated with Strejan an
d Campbell's Method (Journal of Immunology, Vol. 98, 893
Pp. 1967) and the method of Eisen et al. (Journal o.
f American Chemical Society, 75, 4583, 1953)
At that time, it was coupled with 2,4-dinitrobenzenesulfonic acid (DNP). 1 mg of this DNP-As was dissolved in 1 mL of physiological saline in which 10 ¹⁰ pertussis killed bacteria were suspended, and the solution was subcutaneously injected into the foot pads of female rats weighing about 200 g. Five days later, 0.5 mg of DNP-As was dissolved in 0.5 mL of physiological saline and injected into the right and left dorsal muscles. Blood was collected from the abdominal aorta 8 days after the first injection, and the serum was separated and used as rat anti-DNP-As serum. The titer of this antiserum in a rat 24-hour homologous PCA reaction was 1: 512.

(2) Effect on rat allogeneic PCA reaction for 48 hours 7-week-old Wistar male rats were shaved on the back and then diluted 100-fold with physiological saline to obtain the rat anti-DNP-As serum 0.0
Passive sensitization was performed by intradermal administration of 5 mL. Immediately after that, 0.1 g of the above-mentioned test agent was placed on the polyethylene terephthalate surface of a circular polyethylene terephthalate / ethylene / vinyl acetate laminated film having a radius of 1 cm, and it was attached so that this surface was in contact with the shaving part. After 20 hours of sensitization, the above film was peeled off, and the above test agent was applied again in the same manner. Sensitization 24
After a while, peel off the film and use DN as the corresponding antigen.
0.5% Evans blue containing 2 mg / mL P-As (Merck)
A physiological saline solution was intravenously administered at 2.5 mL / kg to induce a PCA reaction.

The leakage of the dye at the site where the intradermal reaction is elicited in this manner is described by Harada et al. (J. Pharm. Pharmacol. 23, 218).
Page, 1971). That is, 1 hour after the antigen injection, the animal was sacrificed, the skin of the PCA reaction part was cut into small pieces, and this was immersed in a mixed solution of 0.3% sodium sulfate aqueous solution 3 volume and acetone 7 volume for 24 hours, and the amount of leaked dye. I asked.

As a control for this test, a control agent (DSCG in each test agent was used instead of each of the above test agents).
Replaced with each base component. However, the composition ratio of each base component was used as the base composition ratio of the original test agent), and the amount of leaked dye was similarly determined. From the measurement results of the amount of leakage dye at the control agent application site (represented by (A) in Formula I) and the amount of leakage dye at the test agent application site (represented by (B) in Formula I), the reaction inhibition rate was calculated by the following formula. Was calculated and the results are shown in Tables 1 and 5. Suppression rate (%) = ((A)-(B)) / (A) × 100 Formula I

From the results of the reaction inhibition rates shown in Tables 1 and 5, it can be seen that the external composition for skin of the present invention exerts a sufficient effect in the treatment of skin inflammation associated with type I allergy.

(Test Example 4) Effect of N-lauroylsarcosine dinitrochlorobenzene on dry skin model of rat N-lauroylsarcosine (manufactured by Nacalai Tesque) and gelled hydrocarbon (manufactured by Bristol-Myers Squibb, trade name " Plastibase '') in a weight ratio of 2:98 to a mortar and kneaded until the whole is uniform and the ointment (hereinafter referred to as "2% L
S-containing plastibase ointment ") was obtained.

The back of 7-week-old Wistar male rats was shaved, and then 0.1 g of the above 2% LS-containing plastibase ointment was added,
It was placed on the polyethylene terephthalate surface of a circular polyethylene terephthalate / ethylene / vinyl acetate laminated film having a radius of 1 cm, and it was attached so that this surface was in contact with the shaving part.

After 24 hours, the above film was peeled off, and 20 μL of a 1% (w / v) acetone solution of 2,4-dinitrochlorobenzene was applied to this site and dried well. Immediately after drying, 0.1 g of the above test agent was placed on the polyethylene terephthalate surface of a circular polyethylene terephthalate / ethylene / vinyl acetate laminated film having a radius of 1 cm, and it was attached so that this surface was in contact with the shaving part.

The film was peeled off 18 hours after application,
6 hours later, the amount of transepidermal water loss (TEWL) at the same site was EVAPOR
It measured using IMETER EP1 (made by SERVOMED), and the measurement result is shown in Tables 1-5. The lower the TEWL value, the higher the therapeutic effect on dry skin, and the unit of TEWL in Tables 1 to 5 is g / (m ² · h). Further, as a control, instead of the test agent, the same test was performed using only an ointment base (plastibase), and the results are shown in Tables 1 to 1.
5 shows.

Further, with respect to normal skin of rats (plastibase ointment containing 2% LS and skin not applied with DNCB acetone solution), nothing was applied, and ointment base
About (Plastic base) only for 24 hours,
Similarly, TEWL was measured, and the results are also shown in Tables 1-5.

From the TEWL values shown in Tables 1 to 5, it is understood that the external composition for skin of the present invention exerts a sufficient effect in treating dry skin.

Test Example 5 N-lauroyl sarcosine
Effect on rat skin barrier hypofunction model using dinitrochlorobenzene N-lauroyl sarcosine and gelled hydrocarbon in weight ratio
Supply it to the mortar at 2:98 and knead until the whole becomes uniform. Ointment (hereinafter referred to as "2% LS-containing plasty base ointment").
Got

Further, crystal violet (manufactured by Wako Pure Chemical Industries, Ltd.) and hydrophilic ointment were supplied to a mortar at a weight ratio of 1:99, and kneaded until the whole became uniform, and the ointment (hereinafter referred to as “1% CV-containing hydrophilic "Ointment").

The back of 7-week-old male Wistar rats was shaved, and then 0.1 g of the above 2% LS-containing plastibase ointment was added,
It was placed on the polyethylene terephthalate surface of a circular polyethylene terephthalate / ethylene / vinyl acetate laminated film having a radius of 1 cm, and it was attached so that this surface was in contact with the shaving part.

The film was peeled off 24 hours after application, and then 1% (w / w of 2,4-dinitrochlorobenzene was added to the shaved portion.
v) 20 μL of acetone solution was applied and dried well. Immediately after drying, 0.1 g of the test agent obtained in the above-mentioned example has a radius of 1 cm.
It was placed on the polyethylene terephthalate surface of the circular polyethylene terephthalate / ethylene / vinyl acetate laminated film, and was attached so that this surface contacts the shaving part.

After 24 hours from application, the film of the test agent was peeled off, and then 0.05 g of the hydrophilic ointment containing 1% CV was placed on the polyethylene terephthalate surface of a circular polyethylene terephthalate / ethylene vinyl acetate laminated film having a radius of 1 cm. Was attached so that the shaving part would contact the shaving part.

After 24 hours from application, the film was removed, and the shaving area was tape-striped eight times with cellophane tape (manufactured by Sekisui Chemical Co., Ltd.) to remove the stratum corneum, and the degree of blueness at the same site was measured with a colorimeter. It was measured.

From the measurement results of the bluishness of the control agent application site (represented by (A) in Formula I) and the blueness of the test agent application site (represented by (B) in Formula I), the bluish inhibition rate was calculated by the following formula. Was calculated. Suppression rate (%) = ((A)-(B)) / (A) × 100 Formula I In addition, the stronger the bluish color, the greater the amount of crystal violet that has penetrated into the epidermal layer, and the skin barrier function deteriorates. The suppression of the bluishness indicates that the skin barrier function was improved, that is, the skin was kept in a healthy state. From the results of the suppression rate of blueness shown in Table 1, it can be seen that the external composition for skin of the present invention has the effect of improving the skin barrier function.

(Test Example 6) The test agents of Examples 28 to 33 were stored at 60 ° C. for 4 weeks, and the concentrations of sodium cromoglycate and glycol salicylate in the preparation before and after storage were measured using a high performance liquid chromatograph. The measurement was performed and the results are shown in Table 4. From the results shown in Table 4, it can be seen that the external composition for skin of the present invention exhibits sufficient storage stability.

[0082]

[Table 1]

[0083]

[Table 2]

[0084]

[Table 3]

[0085]

[Table 4]

[0086]

[Table 5]

[0087]

Since the external composition for skin of the present invention has the above-mentioned constitution, it can exert a sufficient effect in keeping the skin healthy or treating a skin disease.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/352 A61K 31/352 47/06 47/06 47/10 47/10 47/12 47/12 47 / 14 47/14 47/16 47/16 47/18 47/18 47/26 47/26 47/36 47/36 A61P 17/00 A61P 17/00 (31) Priority claim number Japanese Patent Application 2001-384943 ( P2001-384943) (32) Priority date December 18, 2001 (December 18, 2001) (33) Country claiming priority Japan (JP) F-term (reference) 4C076 AA06 BB31 CC18 DD34N DD38N DD42N DD44N DD51N DD52N DD54N DD69N EE23N EE30N FF34 4C083 AC021 AC111 AC121 AC231 AC291 AC331 AC471 AC641 AC661 AC681 AC841 AD311 AD531 CC02 DD22 EE11 4C086 AA02 BA08 DA17 MA03 MA05 MA28 MA63 ZA89 ZA92 ZB13

Claims (9)

[Claims] 1. A composition for external use for skin, comprising sodium cromoglycate and a monoester of a polyhydric alcohol and salicylic acid in a base. 2. The external composition for skin according to claim 1, wherein the monoester of polyhydric alcohol and salicylic acid is glycol salicylate. 3. The external composition for skin according to claim 1, wherein the content of the monoester of polyhydric alcohol and salicylic acid is 1 to 20% by weight. 4. N-acyl sarcosine or a salt thereof, carbon number
Higher fatty acid ester of 10-18 higher fatty acid and alcohol having 1-20 carbon atoms, dicarboxylic acid having 2-10 carbon atoms or salt thereof, hydroxycarboxylic acid having 3-6 carbon atoms and 1-2 carbon atoms
Contains at least one percutaneous absorption enhancer selected from the group consisting of hydroxycarboxylic acid ester with alcohol of 0, fatty acid ethanolamide, glycerin, propylene glycol, polyethylene glycol, urea, glycyrrhizic acid, squalane and mucopolysaccharide. The external composition for skin according to claim 1, 2 or 3, wherein 5. The external composition for skin according to claim 4, comprising at least one percutaneous absorption enhancer selected from the group consisting of glycerin, propylene glycol, urea, squalane and mucopolysaccharide. . 6. The external composition for skin according to claim 1, wherein the base is a water-soluble base. 7. The external composition for skin according to claim 1, wherein the pH is 2 to 7. 8. The external composition for skin according to claim 1, 2, 3, 4, 5, or 6, wherein the pH is 4 to 5. 9. A cosmetic or pharmaceutical product comprising the external composition for skin according to claim 1, 2, 3, 4, 5, 6, 7 or 8.