JP2007332055A - External preparation for skin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an external preparation for skins, which can healthily keep the skins and can topically be applied to exhibit excellent therapeutic effects for skin diseases including atopic dermatitis. <P>SOLUTION: This external preparation for the skins, for topically applying to skin diseases, is characterized by containing sodium cromoglycate and a vitamin B3 compound. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention relates to an external preparation for skin that can keep skin healthy and, when applied locally, exerts an excellent therapeutic effect on skin diseases such as atopic dermatitis.

Sodium cromoglycate (sodium salt of 1,3-bis (2-carboxychromone-5-yloxy) -2-hydroxypropane) suppresses the release of chemical mediators from mast cells in type I allergic reactions It is known as a substance and is used for the treatment of allergic diseases such as allergic asthma by administration by inhalation of inhalation capsules, inhalation solutions and aerosol preparations.

As a treatment method using such cromoglycate sodium, for example, in Patent Document 1, sodium cromoglycate is locally administered to the skin or eye tissue to treat an ophthalmic disease associated with chronic skin disease or allergic or immune reaction. Etc. are disclosed.

Patent Document 2, Patent Document 3 and Patent Document 4 disclose that an external preparation containing sodium cromoglycate is effective for treatment of skin diseases involving dryness or type I allergic reaction. . However, the therapeutic effect of skin diseases by these external preparations containing sodium cromoglycate has not always been sufficient.
JP 52-44242 A JP 11-335281 A JP 11-335282 A JP 2003-246737 A

An object of the present invention is to provide an external preparation for skin that can keep the skin healthy and can exert an excellent therapeutic effect on skin diseases including atopic dermatitis by applying locally. .

The present invention is a skin external preparation for local application to skin diseases, and is a skin external preparation containing sodium cromoglycate and a vitamin B3 compound.
The present invention is described in detail below.

As a result of diligent research, the present inventors have been able to maintain healthy skin by applying a topical skin preparation containing sodium cromoglycate and a vitamin B3 compound locally to skin diseases, and atopy. The present inventors have found that the effect of treating skin diseases such as atopic dermatitis is remarkably improved and has completed the present invention.

The external preparation for skin of the present invention contains sodium cromoglycate and a vitamin B3 compound.

The sodium cromoglycate is a sodium salt of 1,3-bis (2-carboxychromone-5-yloxy) -2-hydroxypropane, and suppresses the release of chemical mediators from mast cells in allergic reactions. Therefore, it exhibits an excellent effect in the treatment of allergic diseases such as allergic asthma.

The preferable lower limit of the content of sodium cromoglycate in the external preparation for skin of the present invention is 0.5% by weight, and the preferable upper limit is 10% by weight. If it is less than 0.5% by weight, the therapeutic effect of skin diseases caused by sodium cromoglycate may be insufficient. Even if it contains more than 10% by weight, the therapeutic effect of the skin disease is not improved, and there may be a problem in dosage form. A more preferred lower limit is 1% by weight, and a more preferred upper limit is 5% by weight.

The said cromoglycate sodium can further improve the skin disease therapeutic effect which cromoglycate sodium has by using together with a vitamin B3 compound.
The vitamin B3 compound is not particularly limited, and examples thereof include nicotinamide, nicotinic acid, nicotinyl alcohol, pharmacologically acceptable derivatives and salts thereof, and the like. Among these, nicotinamide or pharmacologically acceptable derivatives and salts of nicotinamide are preferable, and nicotinamide is more preferable.

The minimum with preferable content of the said vitamin B3 compound in the skin external preparation of this invention is 0.1 weight%, and a preferable upper limit is 20 weight%. If it is less than 0.1% by weight, the effect of the present invention may be insufficient, and even if it contains more than 20% by weight, no improvement in the therapeutic effect of skin diseases is seen, and in terms of formulation May cause problems. A more preferred lower limit is 0.5% by weight, and a more preferred upper limit is 10% by weight.

The external preparation for skin of the present invention preferably further contains a sucrose fatty acid ester. The sucrose fatty acid ester is an ester composed of a reaction product of sucrose and a fatty acid. By using the sucrose fatty acid ester in combination with the sodium cromoglycate and the vitamin B3 compound, the effect of sodium cromoglycate on skin diseases can be further improved. Although it does not specifically limit as said fatty acid, The preferable minimum of the carbon number of a fatty-acid part is 10, and a preferable upper limit is 16. By making the number of carbons within the above range, the effect of sodium cromoglycate on skin diseases is remarkably improved. A more preferred upper limit is 14.
Moreover, the esterification degree of sucrose in the sucrose fatty acid ester is not particularly limited, but a preferable lower limit of the monoester content is 30%. If it is less than 30%, the effect of sodium cromoglycate on skin disease may be reduced.

The minimum with preferable content of the said sucrose fatty acid ester in the skin external preparation of this invention is 0.01 weight%, and a preferable upper limit is 4.5 weight%. If the amount is less than 0.01% by weight, the effect of the present invention may be insufficient. Even if the amount exceeds 4.5% by weight, the therapeutic effect on skin diseases is not improved, and the skin It may become highly irritating and cannot be applied locally to diseased skin. A more preferred lower limit is 0.05% by weight, and a more preferred upper limit is 3.5% by weight.

In the external preparation for skin of the present invention, the base for dissolving and dispersing the above sodium cromoglycate and vitamin B3 compound is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include conventionally known solutions and ointments. Agents, liniments, lotions and the like. Among them, a uniform ointment is preferable. Specifically, 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 Polymers such as coalescence, polyvinyl ether, polyvinyl pyrrolidone, beeswax, olive oil, cacao oil, sesame oil, soybean oil, camellia oil, peanut oil, cow oil, pork oil, lanolin, etc .; 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 alcohol Higher alcohol; polyethylene glycol; surfactants; glycerol, propylene glycol, polyhydric alcohols such as ethylene glycol water, and the like.

The surfactant is not particularly limited, and examples thereof 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 / hardened castor oil, polyoxyethylene sterol / hydrogenated sterol, polyethylene glycol fatty acid ester, polyoxyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, Polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene lanolin and lanolin al Lumpur beeswax derivatives, polyoxyethylene alkyl amines, fatty acid amides, polyoxyethylene alkyl ether phosphoric acid-phosphate, polymer emulsifier, and the like.

As the base used in the external preparation for skin of the present invention, a water-soluble base is preferable. Examples of the water-soluble base include water, glycerin, propylene glycol or a mixture thereof, the above water, glycerin, propylene glycol and polyacrylic. Examples include water-soluble gels to which acid salts and the like are added, water-soluble ointment bases made of polyethylene glycol, and the like.

The external preparation for skin of the present invention may contain other medicinal ingredients as necessary. The other medicinal ingredients are not particularly limited, and examples thereof include steroidal anti-inflammatory agents, nonsteroidal anti-inflammatory agents, antiallergic agents, antihistamines, bactericidal antiseptics, antibiotics, immunosuppressive agents and the like.

The external preparation for skin of the present invention contains, as necessary, inorganic fillers such as kaolin, bentonite, zinc oxide and titanium oxide; viscosity modifiers, anti-aging agents, pH adjusters; buffers; preservatives; You may do it.

The preferable lower limit of the pH of the external preparation for skin of the present invention is 2, and the preferable upper limit is 7. If it is less than 2, irritation may occur at the application site, or precipitation of cromoglycate sodium may occur. If it exceeds 7, problems in dosage form may occur, and decomposition of cromoglycate sodium may occur. A more preferred lower limit is 4, and a more preferred upper limit is 5.

The form of the external preparation for skin of the present invention is not particularly limited, and for example, a cream, gel, jelly, paste, or emulsion in which the above sodium cromoglycate and vitamin B3 compound are dissolved, mixed and dispersed in the base. And liquid form.

Examples of the use of the external preparation for skin of the present invention include pharmaceuticals and cosmetics. When used as the above pharmaceuticals, for example, rough skin, rashes, rashes, sores, irritations, diaper rashes, atopic dermatitis, contact dermatitis, seborrheic dermatitis, Vidar lichen, monetary eczema, housewife eczema, Sunlight dermatitis, insect bite, pruritus, prurigo, drug eruption, poisoning eruption, psoriasis, psoriasis, palmoplantar pustulosis, flat war, luster lichen, bristle erythema saccharosis, gibber rose saccharosis, Erythematosis, erythroderma, discoid lupus erythematosus, systemic lupus erythematosus, pemphigus, pemphigoid, gelling-herpetic dermatitis, alopecia areata, vulgaris vulgaris, sarcoidosis, cutaneous amyloidosis, keloid, thickening It can be used to treat various skin diseases such as sexual scars, wounds, wounds, skin ulcers and hair loss.

The amount of the external preparation for skin use of the present invention varies depending on the type of disease, the degree of symptoms, the size of the affected area, etc., but is preferably about 0.1 to 10 g per day, and this is divided into one or an appropriate number of times. Apply to the affected area.

The method for producing the external preparation for skin of the present invention is not particularly limited, and examples thereof include a method of adding a base substance such as water or propylene glycol to the above sodium cromoglycate and vitamin B3 compound and kneading. It is done.

Since the external preparation for skin of the present invention contains sodium cromoglycate and a vitamin B3 compound, the effect of sodium cromoglycate is enhanced. By applying locally, skin diseases including atopic dermatitis It is possible to provide an external preparation for skin that exhibits an excellent therapeutic effect on the skin.

Hereinafter, embodiments of the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

(Examples 1-25, Comparative Examples 1-10)
Sodium cromoglycate (manufactured by Fukuju Pharmaceutical Co., Ltd.), nicotinamide (manufactured by Organic Synthetic Chemical Industry Co., Ltd.) as vitamin B3 compound, sucrose fatty acid ester, sucrose capric acid ester “SM-1000” (manufactured by Dojin Chemical Co., Ltd., 10 carbon atoms, monoester content of 80% or more), sucrose lauric acid ester “J-1216” (manufactured by Mitsubishi Foods Co., Ltd., 12 carbon atoms of fatty acid portion, monoester content of about 80%), “J-1205” ( Mitsubishi Foods, carbon number of fatty acid part 12, monoester content about 30%), sucrose laurate "J-1201" (Mitsubishi Foods, carbon number of fatty acid part 12, monoester content about 1%) , Sucrose myristic acid ester “J-1416” (manufactured by Mitsubishi Foods, carbon number of fatty acid part 14, monoester content about 80%), Sugar palmitic acid ester “J-1616” (manufactured by Mitsubishi Foods, carbon number of fatty acid part 16, monoester content about 80%), sucrose stearate ester “J-1816” (manufactured by Mitsubishi Foods, carbon of fatty acid part 18, sucrose erucic acid ester “J-2102” (Mitsubishi Chemical Foods Co., Ltd., carbon number 21 of fatty acid part, monoester content about 2%), sucrose behenic acid ester “J -2203 "(Mitsubishi Foods, carbon number of fatty acid part 22, monoester content of about 20%), propylene glycol (Maruishi Pharmaceutical Co., Ltd.) and carboxyvinyl polymer (trade name" Sintalen L ", Wako Pure Chemical Industries, Ltd.) Were kneaded in the blending amounts shown in Table 1 to obtain test agents.
In addition, after mixing each component, an appropriate amount of triethanolamine (manufactured by Nippon Shokubai Co., Ltd.) was added so that the pH would be around 4.7 to obtain a test agent.

(Evaluation)
(1) Property test The obtained test agent was put in a transparent container, and the uniformity was visually determined. The evaluation criteria are as follows.
○: Uniformity was sufficient.
X: It was nonuniform.

(2) Efficacy test The back of 7-week-old Wistar male rats was shaved and then 0.05 mL of a mouse anti-DNP monoclonal antibody (manufactured by Sigma, Lot No. 073K4802) / saline solution of 0.05 mL / mL. Passive sensitization by intradermal administration. 23 hours later, 0.1 g of the test agent was placed on the polyethylene terephthalate surface of a 6.7 cm ² polyethylene terephthalate / ethylene vinyl acetate laminate film, and this surface was in contact with the sensitized part after shaving. Affixed using Shibumini (JOHNSON & JOHNSON). 24 hours after the sensitization, a 0.5% Evans blue saline solution containing 2 mg / mL of DNP human albumin (Sigma, Lot No. 042K760) was intravenously injected at 2.5 mL / kg to induce a PCA reaction. . The Evans Blue physiological saline solution was prepared by dissolving Evans Blue (manufactured by Wako Pure Chemical Industries, Ltd.) in physiological saline and then filtering with MILLEX (manufactured by Millipore, 0.45 μm).

Then, the pigment leakage at the site that caused the intradermal reaction was extracted and quantified according to the method of Harada et al. (J. Pharm. Pharmacol. 23, 218, 1971). That is, the animal is sacrificed 30 minutes after the antigen injection, and after removing the test agent, the skin of the PCA reaction part is chopped, and this is put into a mixed solution of 3 volumes of 0.3% sodium sulfate aqueous solution and 7 volumes of acetone. It was immersed for 24 hours or more, and the amount of leaking dye was determined.
As a control for this test, the amount of the leaked dye was similarly determined using a control agent not containing sodium cromoglycate and nicotinamide instead of the test agent. And the reaction inhibition rate was computed using following formula (1) from the amount of leaking pigment | dyes of a control agent application site | part and a test agent application site | part.
In the following formula (1), A represents the amount of the leaked dye at the control agent application site, and B represents the amount of the leaked dye at the test agent application site.
Inhibition rate (%) = ((A−B) / A) × 100 (1)
The effectiveness of each test agent was evaluated from the obtained inhibition rate.

(3) Irritation test After shaving the back of a 16-week-old Japanese white male rabbit with a clipper, it was confirmed that the skin condition was good before the test. 0.5 g of the test agent was weighed on a 2.5 cm × 2.5 cm lint cloth (manufactured by Kawamoto Sangyo Co., Ltd.), and previously spread evenly on the lint cloth with a spatula, which was used as a test substance. After creating a “#” type wound on the back skin of the rabbit so as not to scratch the dermis with the tip of an 18G needle, the test agent side of the test substance is affixed, and a lint cloth is applied around it. The polyethylene terephthalate surface of a large polyethylene terephthalate / ethylene / vinyl acetate laminate film was covered and fixed with Nichiban (Nichiban Co., Ltd., width 25 mm). In addition, gauze was placed and fixed with Nichiban. The test substance was removed 24 hours after administration, and the irritation was determined according to the following criteria 1 hour later and 48 hours and 72 hours after administration.

A: When evaluated according to the Draize criteria, the erythema score is 1 or less at any of the above determination times.
○: When evaluated according to the Draize criteria, the erythema score is 2 or less at any of the above determination times.
X: The erythema score is 3 or more at any one of the above determination times when evaluated according to the Draize criteria.
(Draize criteria)
0: No erythema 1: Very mild erythema (barely discernable)
2: Clear erythema 3: Moderate to severe erythema 4: From severe erythema to slight crust formation

As shown in Table 1, it can be seen from the results of the property test that a uniform skin external preparation can be obtained when the content of sodium cromoglycate is 10% by weight or less. In addition, from the results of the usefulness test, the test agents of Examples 1 to 25 exhibit a sufficient effect in treating skin inflammation involving type I allergic reaction, in particular, sodium cromoglycate and vitamin B3 compound. It turns out that the effect improves by using together, and the effect improves further by using sucrose fatty acid ester together.

ADVANTAGE OF THE INVENTION According to this invention, the skin can be kept healthy and can provide the skin external preparation which exhibits the outstanding therapeutic effect with respect to skin diseases including atopic dermatitis by applying locally. .

Claims (7)

A skin external preparation for topical application to a skin disease, comprising sodium cromoglycate and a vitamin B3 compound. The skin external preparation according to claim 1, comprising 0.5 to 10% by weight of sodium cromoglycate and 0.1 to 20% by weight of vitamin B3 compound. The external preparation for skin according to claim 1 or 2, wherein the vitamin B3 compound is nicotinamide. Furthermore, sucrose fatty acid ester is contained, The skin external preparation of Claim 1, 2, or 3 characterized by the above-mentioned. The skin external preparation according to claim 4, comprising 0.01 to 4.5% by weight of a sucrose fatty acid ester. The skin external preparation according to claim 4 or 5, wherein the sucrose fatty acid ester has 10 to 16 carbon atoms in the fatty acid moiety. The skin external preparation according to claim 4, 5 or 6, wherein the sucrose fatty acid ester has a monoester content of 30% or more.