External skin preparation

FIELD: medicine.

SUBSTANCE: external skin preparation contains as active components a ferrous compound and a compound chosen from 5-aminolevulin acid, salt of 5-aminolevulin acid, ester of 5-aminolevulin acids, ester of salt of 5-aminolevulin acids, N-acyl-5-aminolevulin acids, salts of N-acyl-5 aminolevulin acid and ester of N-acyl-5-aminolevulin acid. The ferrous compound is chosen from iron (II) citrate, sodium-iron citrate, ammonium-iron citrate, iron acetate, iron oxalate, iron (II) succinate, sodium-iron succinate and citrate, iron (II) pyrophosphate, iron (III) pyrophosphate, heme iron, iron dextrane, iron lactate, iron (II) gluconate, sodium-iron diethylene triaminepentaacetate, ammonium-iron diethylene triaminepentaacetate, ethylenediaminetetraacetate sodium-iron ethylene aminpentaacetate, ammonium-iron ethylene aminpentaacetate, iron triethylene tetraamine, sodium-iron dicarboxymehtyl glutamate and ammonium-iron dicarboxymehtyl glutamate.

EFFECT: improved skin look, prevention or reduction of roughness, dryness, wrinkles, flabbiness, and pigment spots, efficient for atopic dermatitis.

16 cl, 2 ex, 2 dwg

 

The technical field to which the invention relates.

[0001] the Present invention relates to a tool for external application to skin having excellent effects of improving skin appearance, such as the prevention/reduction of agrability skin, dry skin, wrinkles, sagging skin and age spots on the skin and improve the update of the surface layer of the epidermis, as well as a means external application to skin, which has an excellent effect improvement in skin diseases such as atopic dermatitis, and in particular to means external application for skin that uses a combination of 5-aminolevulinic acid or its derivatives with compounds of iron.

The level of technology

[0002] Known means of external application for skin, aimed at the prevention and reduction of agrability skin. Examples of such means of external application for skin are tools outdoor use to reduce agrability skin that contain alum, salt, calcium and magnesium (see Japanese laid patent application No. 2004-284962), and an agent for preventing/reducing agrability skin consisting of N-α-benzoyl-L-arginine-ethyl-ester (see Japanese laid patent application No. 2000-281556).

[0003] Also known is the use of 5-aminolevulinic acid or its derivatives as GE is bicicov (for example, see Japanese laid patent application No. 08-081322), plant growth regulators (for example, see Japanese laid patent application No. 07-53487), means external use for the care of the head (for example, see Japanese laid patent application No. 11-116446) etc.

[0004] However, an unknown tool external use for skin care containing 5-aminolevulinic acid or its derivatives, as well as the effect of 5-aminolevulinic acid or its derivatives on rough skin.

[0005] Patent document 1: Japanese laid patent application No. 2004-284962.

Patent document 2: Japanese laid patent application No. 2000-281556.

Patent document 3: Japanese laid patent application No. 08-081322.

Patent document 4: Japanese laid patent application No. 07-53487.

Patent document 5: Japanese laid patent application No. 11-116446.

Disclosure of inventions

The goal achieved by the invention

[0006] Despite the popularity of using 5-aminolevulinic acid or its derivatives as herbicides, plant growth regulators, means external use for the treatment of the head, unknown means external use on skin care products containing 5-aminolevulinic acid or its derivatives, as well as the effect of 5-aminolevulinic acid and its derivatives on rough skin. The purpose of this izopet the tion is the provision of means external application for skin containing 5-aminolevulinic acid or its derivatives as active ingredients and which has an excellent effect on the prevention/reduction of agrability skin, dry skin, wrinkles, sagging skin and age spots on the skin and to improve the update of the surface layer of the epidermis; and the effect of improvement in skin diseases such as atopic dermatitis.

A means to a goal

[0007] the previously Known means of external applications for treatment of the head (the hair reducing agents), containing as an active ingredient 5-aminolevulinic acid or its derivatives may not be applied continuously for the following reasons: they cause damage to the hair if not used in accordance with the assigned dose and technique, which leads to problems such as splitting ends and reducing the amount of hair, in addition, a requirement was to protect from light during use. The author of the present invention have found that these problems can be avoided by using 5-aminolevulinic acid or its derivatives together with iron compounds.

[0008] the Author of the present invention conducted a thorough investigation and found that a mixture of 5-aminolevulinic acid or its derivatives with iron compounds has an effect to improve the appearance of skin, t is Kim as prevention/reduction of agrability skin, dry skin, wrinkles, sagging skin and age spots on the skin and improve the update of the surface layer of the epidermis, as well as the effect of improvement in skin diseases such as atopic dermatitis

[0009] in Other words, the present invention relates to: (1) means external application to skin, which, as the active component contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and iron compounds; (2) the means of external application for skin according to the above item (1), which further contains urea as an active ingredient; (3) the means of external application for skin according to the above-mentioned paragraphs (1) or (2), in which the connection of iron is one or more compounds selected from the group consisting of citrate, iron (II)citrate sodium-ferric ammonium citrate iron, iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron dicarboxylate sodium-iron and decarboxylation ammonium.

[0010] the Present invention also relates to (4) medicinal drug for preventing/reducing agrability skin, as the active component contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and iron compounds; and (5) medicinal drug for preventing/reducing agrability skin according to the above item (4), where as compounds of iron used one or more compounds selected from the group consisting of citrate, iron (II)citrate-iron, ammonium citrate iron, iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium.

[0011] furthermore, the present invention relates to: (6) medicinal drug to prevent/reduce dryness of the skin, which as the active component contains one or more compounds selected and the group, consisting of 5-aminolevulinic acid, its salt and a derivative, and iron compounds; and (7) drug-drug for preventing/reducing dryness of the skin according to the above item (6), where as compounds of iron used one or more compounds selected from the group consisting of citrate, iron (II)citrate sodium-ferric ammonium citrate iron, iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium.

[0012] the present invention relates to: (8) medicine to prevent/reduce wrinkles and age spots, as the active component contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and iron compounds; and (9) medicine to prevent/reduce wrinkles/age spots according to the above item (8), in which oterom as compounds of iron used one or more compounds selected from the group consisting of citrate, iron (II)citrate sodium-ferric ammonium citrate iron, iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium.

[0013] the Present invention further relates to: (10) the method of preventing/reducing agrability skin containing percutaneous insertion of external application to skin, which, as the active component contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and compounds of iron.

[0014] the Present invention also relates to: (11) the method of preventing/reducing dryness of the skin, containing percutaneous insertion of external application to skin, which, as the active component contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and connections jelly is A.

[0015] the Present invention further relates to: (12) the way to prevent/reduce wrinkles/age spots containing percutaneous insertion of external application to skin, which, as the active component contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and compounds of iron.

[0016] the Present invention also relates to: (13) the means of improvement in atopic dermatitis, which, as the active component contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and iron compounds; and (14) means improvement in atopic dermatitis according to the above paragraph (13), where as compounds of iron used one or more compounds selected from the group consisting of citrate, iron (II)citrate sodium-ferric ammonium citrate iron, iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate and mania-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium.

[0017] the Present invention further relates to: (15) way of improvement in atopic dermatitis containing percutaneous insertion of external application to skin, which, as the active component contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and compounds of iron.

[0018] the Present invention also relates to: (16) the complex of means external application to skin, comprising a first agent which contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and the second agent which contains a compound of iron; (17) the complex of means of external application for skin according to the above item (16), in which the first and/or second agent further comprises urea; and (18) the complex of means of external application for skin according to the above items (16) or (17), in which the connection of iron is one or more compounds selected from the group consisting of citrate, iron (II)citrate sodium-ferric ammonium citrate iron, iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate is Eliza (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium.

[0019] the Present invention further relates to: (19) the method of preventing/reducing agrability skin containing the percutaneous introduction of a first agent which contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and the second agent which contains a compound of iron; (20) the method of preventing/reducing dryness of the skin, containing the percutaneous introduction of a first agent which contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and the second agent, which contains a compound of iron; (21) the way to prevent/reduce wrinkles/age spots containing the percutaneous introduction of a first agent which contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and the second agent which contains a compound of iron; and (22) SP the soba improvement in atopic dermatitis, containing the percutaneous introduction of a first agent which contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and the second agent which contains a compound of iron.

A brief description of graphic materials

[0020] [1] Figure 1 is a photograph showing an example of a clinical trial means external application for skin according to the present invention. The photo was taken five days after the start of application of the sample composition 1. The treated cheek (cheek on the left side of Figure 1) skin became elasticity and dryness decreased compared with the cheek without treatment (cheek on the right side of Figure 1). In addition, the treated cheek (cheek on the left side of Figure 1) is tightened compared to the cheek without treatment (cheek on the right side of Figure 1).

[Figure 2] Figure 2 is a set of photos showing an example of a clinical trial means external application for skin according to the present invention. The left photograph is a photograph of your face before applying the sample composition 1, and the right photo is of the person 14 days after the start of application of the sample composition 1. After applying the redness and pigmentation processing decreased compared with the state before application.

[Figure 3] Figure 3 the submitted is a pictures, showing an example of a clinical trial means external application for skin according to the present invention. The left photo is a photo of the inside of the elbow before applying the sample composition 1, and the right picture is a picture of the inner side of the elbow 7 days after the start of application of the sample composition 1. After applying the redness and pigmentation processing decreased compared with the state before application, thus the appearance of the skin almost normal.

[Figure 4] Figure 4 is a set of photos showing an example of a clinical trial means external application for skin according to the present invention. The left photograph is a photograph armpits before applying the sample composition 1, and the right photo is a photo armpit 7 days after the start of application of the sample composition 1. After applying the redness and pigmentation processing decreased compared with the state before application, thus the appearance of the skin almost normal. In addition, pictures are not visible scratches, as it stopped the itch.

The best examples of carrying out the invention

[0021] the Means of external application for skin according to the present invention are not particularly limited to it as the active component contains one or more compounds selected and the group, consisting of 5-aminolevulinic acid, its salt and derivatives thereof, and compounds of iron. The above aminolevulinate acid is also known as Delta-aminolevulinate acid and represents one of the amino acids of the formula HOOC-(CH2)2-(CO)-CH2-NH2(hereinafter also referred to as 5-ALA). This 5-aminolevulinate acid is widely distributed in different living organisms, you can usually get the biosynthesis using synthetase 5-aminolevulinic acid from succinyl COA and glycine. This 5-aminolevulinate acid is also known as an intermediate product in the biosynthesis of porphyrin. Examples of salts of 5-aminolevulinic acid in the present invention include the salts of such acid residue, as hydrochloride, phosphate, nitrate, sulfate, acetate, propionate, butyl, valerate, citrate, fumarate, maleate and malate; and salt-based metals, such as sodium salt, potassium salt and calcium salt. Preferably, these substances are used in the form of aqueous solutions, suspensions or powders on the application site and create the same effect as 5-aminolevulinate acid.

[0022] Examples of derivatives of 5-aminolevulinic acid, used as active ingredients in a medium external application for skin and complex means of external application for skin according to the present invention are ester 5-aminolevulinic the th acid, N-acyl-5-aminolevulinate acid. Examples of ester of 5-aminolevulinic acid are substituted for the choice of linear, branched or cyclic alkilany ester having 1-24 carbon atoms, preferably, for example, esters of 5-aminolevulinic acid, which radical of ester is a metal group, ethyl group, isopropyl group, n-hexoloy group, tsiklogeksilnogo group, n-heptylene group, n-aktiline group, n-naniloa group, n-dodecyloxy group, n - hexadecyl group, benzyl group, fenetylline group, 3 - phenylpropyl group, hydroxyethylene group or ethoxyethylene group. In addition, examples of the substituent in these alkyl groups are hydroxyl group, CNS group, phenyl group, benzyl group or hydroxymethylene group. Next, an example of N-acyl-5-aminolevulinic acid is a compound in which the amino group of 5-aminolevulinic acid allyawan, for example, alkanoyloxy group, an aromatic acyl group, benzyloxycarbonyl group and the like, each of which has 1-24 carbon atoms. Further preferred examples of N-acyl groups are especially acetyl group, n-pentanolide group, n-hexanoyl group, n-nonantola group, benzoline group and b is silicicola group.

[0023] an ester of 5-aminolevulinic acid and N-acyl-5-aminolevulinic acid can be obtained well-known methods of synthesis, for example, methods described in Japanese laid out application No. 4-9360. In addition to chemical synthesis can be obtained by industrial methods using microorganisms or enzymes. In addition, robocity product containing the target product obtained in the production process, can also be used without separation and purification, if robocity product does not contain toxic substances. And 5-aminolevulinic acid and its salt, and derivatives thereof can be used alone or by mixing two or more of them. The total content of 5-aminolevulinic acid, its salt or derivative, forming part of the means of external application for skin according to the present invention is usually 0.01 to 40 wt.%, preferably 0.1 to 10 wt.% all funds external application to the skin.

[0024] the composition of iron in the present invention are not particularly limited, if it is a connection that has iron in its molecule. Examples of compounds include iron citrate, iron (II)citrate-iron, citrate of ammonium-iron, iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, lactate W is found gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium-iron, ethylendiaminetetraacetic of sodium iron ethylenediaminetetraacetate ammonium-iron, Triethylenetetramine iron, decarboxylation sodium-iron, decarboxylation ammonium citrate halinowego iron formate, iron (II)formate, iron (III)oxalate potassium-ammonium-iron (III)sulfate iron (II)sulfate iron (III)ammonium sulfate, iron, and carbonate of iron (III)chloride iron (II)chloride iron (III)pyrophosphate of iron (III) and iron oxide. Among them, preferred diethylenetriaminepentaacetate sodium-iron and diethylenetriaminepentaacetate ammonium-iron. Each of these iron compounds can be used alone or by mixing two or more of them. The total content of compounds of iron, part of the funds external application for skin according to the present invention is usually 0.01 to 80 wt.%, preferably 0.5 to 50 wt.% all funds external application to the skin.

[0025] the Means of external application for skin according to the present invention acts on the sebaceous glands of the skin, stimulates the secretion of sebum. In addition, the means of external application for skin according to the present invention affects the cells of the epidermis and on chitin cells, activating them. Predpolagaete is, the result of this are the effects of improving skin condition as prevention/reduction of agrability, dry skin, wrinkles, sagging skin and age spots on the skin and improve the update of the surface layer of the epidermis. Therefore, a means of external application for skin according to the present invention can be used as a drug for preventing/reducing agrability skin, the drug to prevent/reduce skin dryness and medication to prevent/reduce wrinkles/age spots. The term "drug to prevent/reduce" in the phrase "a drug for preventing/reducing agrability skin, the drug to prevent/reduce skin dryness and medication to prevent/reduce wrinkles/blemishes" in the present invention means a drug to prevent and/or reduce". Also, the term "wrinkles/age spots" means "wrinkles and/or liver spots".

[0026] in Addition, a means external application for skin according to the present invention has the effect of improvement in skin diseases such as atopic dermatitis, eczema and diskeratoz. Specifically, this is manifested in the effect of decreasing the dryness of the skin, pigments and skin, skin itching, etc. caused by skin diseases such as atopic dermatitis, eczema and diskeratoz. Therefore, a means of external application for skin according to the present invention can be used as improving medication for skin diseases such as atopic dermatitis, eczema and diskeratoz.

[0027] means For external application for skin according to the present invention does not require that it contain urea, however, the additional inclusion of urea as the active ingredient preferably. Urea exists in the form of colorless or white crystals or crystalline powder, easily soluble in water, soluble in ethanol and as a means of external application can be produced in many kinds of dosage forms, such as lotions and creams. Besides, the urea has a high affinity to the skin and therefore it has a suitable property as a component of the means of external application for skin. Although it depends on the raw material and other components with which it is used, the urea may be added to the medium external application for skin according to the present invention in a ratio of 0.01-40 wt.%, preferably 0.1 to 10%. Directly for the application can be used urea in the sale.

[0028] the Complex of external PR the application for skin according to the present invention consists of a first agent, which contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salts and derivatives thereof; and a second agent which contains a compound of iron. Due to the separation of the first agent containing 5-aminolevulinic acid, etc. and the second agent containing a compound of iron, the activity of 5-aminolevulinic acid, etc. will last longer. Despite the fact that the number of 5-aminolevulinic acid, its salt or its derivative and their derivatives contained in the first agent is not particularly limited, the total amount is usually 0.01 to 40 wt.%, preferably 0.1 to 10 wt.% from the first agent. Despite the fact that the amount of iron compounds in the second agent is not particularly limited, usually the total amount is 0.01-80 wt.%, preferably 0.5 to 50 wt.% from the second agent.

[0029] Further, when the first agent and the second agent of the means for external application for skin according to the present invention are used in combination, achieves the same effect as when using the external application for skin according to the present invention. Therefore, the complex of means of external application for skin according to the present invention can be used as a complex drug that prevents/ reduces rough skin, complex drug is marketed drugs prevent/reduce skin dryness, complex drugs that prevent/reduce wrinkles/age spots, and complex drugs that improve the condition of skin diseases such as atopic dermatitis, eczema and diskeratoz.

[0030] For the first agent and/or the second agent of the means for external application for skin according to the present invention does not require that it contain urea, however, the additional inclusion of urea is preferred. The amount of urea contained in the first agent and the second agent is not particularly limited, and may be added urea in the ratio of 0.01-40 wt.%, preferably 0.1 to 10 wt.%.

[0031] a means external application for skin according to the present invention, as well as to the first agent and the second agent of the means for external application for skin according to the present invention in addition to the above-mentioned 5-aminolevulinic acid, its salt or derivative, compounds of iron and urea can be added one or more of the various components typically used in drugs and medical cosmetics, in the quantity in which they do not affect the effect of the present invention. It can be water components, oil components, the powder components, chemical agents, such as surface-AK is active substances, moisturizing agents, thickeners, dyes, perfume, pH regulators, antioxidants, antiseptics or protection from ultraviolet radiation, and anti-inflammatory agents.

[0032] Examples of the water components are water, lower alcohol (methanol, ethanol, denatured ethanol, propanol, isopropyl alcohol) and other

Examples of oil components are of higher fatty acids (stearic acid, palmitic acid, myristic acid, lauric acid and their esters, higher alcohols (cetanol, lanolin alcohol, stearyl alcohol, cetosteatil alcohol and other), and wax (paraffin wax, microcrystalline wax, zeresenay wax, polyethylene wax, beeswax, vegetable wax, Carnauba wax, wax candelilla and others), natural or synthetic oil substances (squalene, liquid paraffin, lanolin or its derivatives, olive oil, oil from the fruit of Camellia, cotton seed, oleography alcohol, castor oil, vaseline, ester of adipate of diatexite, silicone oil, fluorine oil, and so on).

[0033] examples of the powder components are aluminum powder, powders of titanium oxide, powders of oxides of zinc, powders of iron oxides, acrylic powders, microspheres of silica, talc, sericite and other

Examples of the surfactant is of komponentov are complex arbitarily a fatty acid ester, complex glycerin fatty acid ester, complex polyglycerins a fatty acid ester, a complex of propylene glycol ester of fatty acids, complex polyoxyethylenesorbitan a fatty acid ester, complex polyoxyethylenesorbitan a fatty acid ester, complex polyoxyethyleneglycol a fatty acid ester, complex polietilenglikolya a fatty acid ester, complex polyoxyethyleneglycol ether complex polyoxyethylene-polyoxypropylene ether complex polyoxyethyleneglycol ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylenated beeswax, polyoxyethylenated lanolin, polyoxyethylenated, polyoxyethylenated derived lecithin, polymeric emulsifiers and other

[0034] examples of the moisturizing ingredients are polyhydric alcohols such as glycerin, propylene glycol, 1,3-butyleneglycol, dipropyleneglycol, ethylene glycol, 1,4-butyleneglycol, diglycerin, triglycerin, sorbitol or its derivative, a polyethylene glycol; as well as glucose, maltose, maltitol, sucrose, fructose, threitol, erythritol, sorbitol, a sugar produced by the breakdown of starch, hyaluronic acid, chondroitin sulfate, hydrolyzed collagen, hydrolyzed elastin, carboxymethylchitin, casein sodium, mucin, is glycosphingolipid etc.

[0035] Examples of thickeners are carboxyquinolone, SP gel (CP jelly), carboxymethylcellulose, carageenan, sodium alginate, bentonite, veegum, synthetic hectorite, etc.

[0036] Examples of antioxidants are equivalent (EIT), butylhydroxyanisole (BHA), sodium pyrosulfite, sodium bisulfate, tocopherol, edetate sodium, ascorbic acid, isopropylmalate etc.

[0037] Examples of the pH regulators are citric acid, lactic acid, tartaric acid, phosphoric acid, etc.

Examples of antihistamines include diphenhydramine hydrochloride, the hydrochloride of isothipendyl etc.

[0038] Examples of antiseptics are methyl, ethyl, propyl and butyl esters of n-hydroxybenzoic acid, Phenoxyethanol, o-phenylphenol, deshidratada acid or its salts, n-cresol, m-cresol, o-chloro-m-Xylenol etc.

[0039] Examples of means of protection from ultraviolet radiation are ascorbic acid or its derivatives, isoperla acid or its salts, oxybenzoyl or its derivatives, n-aminobenzoic acid or its derivatives, rocanova acid or its derivatives, kojic acid, dibenzoylmethane or its derivatives, n-metaxalona acid or its derivatives, granular titanium oxide, granular zinc oxide, granular iron oxide.

[0040] the measures anti-inflammatory agents are glycyrrhetic acid or its derivatives, glycyrrhizin acid or its derivatives, guaiazulene or its derivatives, bisabolol, geranin, extracts of horse chestnut, aloe extracts, etc.

[0041] Each of the aforementioned components or agents can be used individually or mix two or more of them.

[0042] with regard to the dosage form tool external application for skin according to the present invention or the first agent and the second agent of the means for external application for skin according to the present invention, it may be either in the form of powders, liquids and ointments. Dosage forms, such as lotions, emulsions, creams (creams, gels and aerosols can be made of commonly used methods (e.g., by the methods prescribed in the Pharmacopoeia of Japan, 12 edition). It is also a means of external application for skin according to the present invention can be incorporated in liposomes. The methods included in the liposome is not particularly limited and is described, for example, in Japanese laid out application No. 11-199488, etc. In the manufacture in the form of aqueous solutions, for example lotions or creams (ointments), to prevent the decomposition of 5-aminolevulinic acid or its salts, or its derivative is preferable to produce the means of external application for skin, paying attention to avoid alkalizing. In the case of alkalizing decomposition can pre order to avert by removing oxygen. If you follow this, then 5-aminolevulinate acid, or a salt thereof, or derivative can be used in combination with commonly used components of liquids or ointments.

[0043] Although the method of application external application for skin according to the present invention has no particular limitation, it is preferable that a means external application for skin according to the present invention was administered transdermally to the skin by means of spraying, application or poultices. Also preferably percutaneous introduction using the system of drug delivery, such as iontophoresis, because it stimulates the absorption of a drug skin tissues and increases the coefficient of absorption of the drug.

[0044] For the method of application of the means for external application for skin according to the present invention has no particular restriction and can be adapted in the following ways: method containing mixing the first agent and the second agent, and applying the mixture on the skin; the method containing the simultaneous application to the skin of the first agent and the second agent; the method that contains the application to the skin of the first agent and then applying the second agent on the same site; and the method containing the application to the skin of the second agent and then applying the second agent on the t the t the same plot. In addition, although the method that contains the introduction of the first agent and the second agent, special is not limited to, such methods as sputtering, applique or a poultice on the skin or ways of using the system of drug delivery, such as iontophoresis, preferred.

[0045] with regard to the dosing means external application for skin according to the present invention and the first agent and the second agent of the means for external application for skin according to the present invention, there are no special restrictions until it matches the level at which is provided the effect on rough skin. However, in the case of application to the skin preferably means external application to the skin so that 5-aminolevulinic acid or its salt and a derivative is introduced in an amount of 10 μg-10 mg, preferably 100 μg to 5 mg, even more desirable 1-5 mg per 10 cm2skin equivalent, representing the hydrochloride of 5-aminolevulinic acid. The dosage of compounds of iron, combined with 5-aminolevulinic acid, etc. is 50 μg to 50 mg, preferably 500 μg to 25 mg, still more desirable 5-25 mg iron equivalent under the same conditions.

As for the order of insertion of external application for skin according to the present invention and the first agent and the second agent of the means for external application the Oia for skin of the present invention, the following method is preferred, but not limiting example of the method containing the percutaneous insertion of external application for skin according to the present invention or the first agent and the second agent of the means for external application for skin according to the present invention in the evening or at night, for example, through applications, and flushing the same evening.

[0046] the Feature of means external application for skin according to the present invention and of the means for external application for skin according to the present invention is that when processing them, there is no need to adhere strictly to the darkness, as with the introduction of only 5-aminolevulinic acid (via applications etc). However, it is preferable to avoid exposure to strong light sources, such as the scorching sun. When using the external application for skin according to the present invention and of the means for external application for skin according to the present invention in many cases already on the third day observed effects enhance the appearance of the skin, such as reducing agrability, dry skin, wrinkles, sagging skin and age spots on the skin, improving the update of the surface layer of the epidermis and the effect of improvement in skin diseases such as atopic dermatitis. The drug mo is but to use continuously, but in the case of achieving sustainable results can temporarily stop the introduction and three months to renew again to get the same result.

[0047] the Methods of the present invention are the following: how to prevent/reduce agrability skin containing percutaneous insertion of external application to skin, which, as the active component contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and iron compounds; a method of preventing/reducing dryness of the skin, containing percutaneous insertion of external application to skin, which, as the active component contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salts and derived, and compounds of iron; the way to prevent/reduce wrinkles/age spots containing percutaneous insertion of external application to skin, which, as the active component contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and compounds of iron; the way of improvement in atopic dermatitis containing percutaneous insertion of external application for skin that is active is komponentov contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and iron compounds; a method of preventing/reducing agrability skin containing the percutaneous introduction of a first agent which contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and the second agent which contains a compound of iron; the way to prevent/reduce dryness of the skin, containing the percutaneous introduction of a first agent which contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salts and their derivative, and the second agent which contains a compound of iron; the way to prevent/reduce wrinkles/age spots containing the percutaneous introduction of a first agent which contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and the second agent which contains a compound of iron; and the way of improvement in atopic dermatitis containing the percutaneous introduction of a first agent which contains one or more compounds selected from the group consisting of 5-aminolevulinic acid, its salt and a derivative, and the second agent which contains a compound of iron. For percutaneous introduction of these Pervov the agent and the second agent are no special restrictions and can be adapted in the following ways: method containing mixing the first agent and the second agent, and applying the mixture on the skin; the method containing the simultaneous application to the skin of the first agent and the second agent; the method that contains the application to the skin of the first agent and then applying the second agent on the same site; and the method containing the application to the skin of the second agent and then applying the second agent on the same plot.

[0048] the Following is a detailed description of the present invention based on examples, but the technical scope of the present invention, these examples are not limited.

Example 1.

[0049] 1.5 g of the hydrochloride of 5-aminolevulinic acid, 3 g of urea and 1 g of citrate of iron (II) thoroughly stirred in 20 ml of purified water in which were dissolved 4% of 1,3-butyleneglycol and 0.15% methylparaben, to prepare a sample of the compound 1.

About 2 ml of the sample composition 1 was applied onto the faces of the subjects (8 female adults) every night. After applying the sample composition was left on the face for 30 minutes-1 hour, after which the same evening face washed to flush out the sample composition.

Not observed the usual strict conditions protect from light, supported when using only 5-aminolevulinic acid and its derivatives, when this was not observed hair loss in a partial dose. On the fifth day of p is after the beginning of application of each of the eight participants assessed the example 1 composition. These results are shown next.

Participant 1: only the right half of his face was exposed to the effect of sample composition 1. The treated areas of the skin become elastic and less dryness. Also processed cheek (cheek on the left side of Figure 1) is tightened compared to the cheek without processing.

Participant 2: the skin became elastic. Nasolabial folds running from the nose to the sides of the mouth, become less deep. For longer use a sample of the compound 1 increased excretion of fat and decreased dry skin. Cosmetics began to go better.

Participant 3: the skin became elastic. Nasolabial folds become less deep. The wrinkles around my eyes have disappeared. Cosmetics began to go better.

Participant 4: the skin became elastic. Complexion brightened up.

Participant 5: the skin became elastic. Decreased dry skin. Cosmetics began to go better.

Participant 6: the skin became elastic. The skin was moist.

Participant 7: without any changes.

Participant 8: without any changes.

As noted above, six of the eight participants noted subjective improvement in skin condition, such as skin elasticity. As follows from the comment of the member 2, the means of external application for skin according to the present invention has the effect of stimulating the activity of the sebaceous glands. It is assumed that the result I have is improving skin elasticity, reducing dryness of the skin, smoothing nasolabial folds, etc. with regard to participant 1, who atopic dermatitis, his skin became elastic, and less dryness. Consequently, this means that the tool external application for skin according to the present invention is also effective for preventing/reducing agrability skin, dry skin, wrinkles and sagging skin in atopic dermatitis. In addition, as in the case of participant 4 was observed lightening of the complexion.

Example 2

[0050] a sample of the compound 1 in example 1 was applied every evening once in the affected areas in six patients with atopic dermatitis (participants 9-13 and member 1 of example 1)and two patients with chronic eczema (participants 14-15) in an amount of about 1 ml per 100 cm2skin. After applying the sample was left for 30 minutes-1 hour, and the same evening the areas that suffered the composition was rinsed to wash away the sample composition. Affected areas 1-2 weeks after the start of injection of the sample composition 1 was compared with the affected areas before the introduction, and the inventor, which the doctor has pronounced judgment and assessment of "significant improvement", "improvement", "unchanged", "deterioration". Judgment and assessment imposed using levels reduce redness, pigmentation and itching of the skin and soften the skin in the quality of the ve indicators. As a result, four out of six patients with atopic dermatitis was "significant improvement", the other two patients ' improvement', and one of two patients with chronic eczema was "significant improvement", the other "improvement". From this result it is obvious that the means of external application for skin according to the present invention improves not only in atopic dermatitis, but also improves the skin condition eczema and diskeratoz.

Next, three of the eight patients with atopic dermatitis will be described in detail.

Participant 1: "improving"

Suffering from atopic dermatitis. Only the right half of the face was treated sample composition 1, and the skin in the treated area became elastic, and dryness decreased. In addition, the skin in the treated area became softer, and processed cheek tightened compared to the cheek without processing.

Participant 9: "significant improvement"

Participant 9 suffers from atopic dermatitis since elementary school, several tens of years, periodically uses steroid tools outdoor applications. The main affected areas of the face and neck. The skin on the affected areas was strong, with redness and pigmentation (see Figure 2, a photograph of a face left), which was accompanied by itching, had the typical appearance when atopy. Participant 9 was assigned to use the sample composition 1 from the local to steroid tool external use, three days later, the use of steroid funds was discontinued as itching disappeared. After this was used only a sample of the compound 1, redness and pigmentation in the affected areas has decreased and the skin became soft (see Figure 2, a photograph of a face on the right). Also decreased wrinkles and age spots on skin.

Participant 10: "significant improvement".

Participant 10 suffers from atopic dermatitis since elementary school, several tens of years, periodically uses steroid tools outdoor applications. The main affected areas are the underarms and inner side of the elbow. The affected areas was itching, and the skin was firm, with redness, pigmentation and scratches (see the left picture in figure 3 (the inner side of the elbow) and Figure 4 (armpit)), demonstrated the typical appearance when atopy. Participant 10 was assigned to use the sample composition 1 in conjunction with steroid by means of external application, and in three days using steroid funds was discontinued as itching disappeared. After this was used only a sample of the compound 1, redness and pigmentation in the affected areas has decreased, the skin was soft and had become almost normal appearance (see right picture in figure 3 (the inner side of the elbow) and Figure 4 (armpit)).

Industrial applicability

[0051] a Means external application for skin according to the present is obreteniyu, containing 5-aminolevulinic acid and its derivatives, has the effect of improving the appearance of the skin, for example, prevent/reduce agrability skin, dry skin, wrinkles, sagging and age spots and improve the update of the surface layer of the epidermis; and the effect of improving the condition of skin with dermatitis, such as atopic dermatitis. In addition, since 5-aminolevulinic acid and its derivatives are used together with the compound of iron in the tool external application for skin according to the present invention, there is no strict requirements for the protection from light on the place of use of external application for skin according to the present invention and its use is simple. Moreover, with regard to effects enhance the appearance of the skin, for example, prevent/reduce agrability skin, dry skin, wrinkles, sagging and age spots and improve the update of the surface layer of the epidermis, and also the effect of improving the condition of skin with skin diseases such as atopic dermatitis, the tool external application for skin according to the present invention exhibits a remarkable effect, equal or stronger than the actions observed when using one of 5-aminolevulinic acid or its derivatives.

1. Means external application for skin is, containing as active ingredients a compound of iron and a compound selected from 5-aminolevulinic acid, salts of 5-aminolevulinic acid, a complex ester of 5-aminolevulinic acid, ether complex salt of 5-aminolevulinic acid, N-acyl-5-aminolevulinic acid, salts of N-acyl-5-aminolevulinic acid and a complex ester of N-acyl-5-aminolevulinic acid, with a compound selected from iron citrate, iron (II)citrate sodium-ferric ammonium citrate iron, iron acetate, iron oxalate, succinate of iron (II), succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium-iron.

2. Means external application for skin according to claim 1, which further contains urea as the active component.

3. A means to prevent/reduce agrability skin containing as active ingredients a compound of iron and a compound selected from 5-aminolevulinic acid, salts of 5-aminolevulinic acid, Slonov the ester of 5-aminolevulinic acid, of ester salt of 5-aminolevulinic acid, N-acyl-5-aminolevulinic acid, salts of N-acyl-5-aminolevulinic acid and a complex ester of N-acyl-5-aminolevulinic acid, with a compound selected from iron citrate, iron (II)citrate sodium-ferric ammonium citrate iron, iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium-iron.

4. A means to prevent/reduce dryness of the skin, containing as active ingredients a compound of iron and a compound selected from 5-aminolevulinic acid, salts of 5-aminolevulinic acid, a complex ester of 5-aminolevulinic acid, ether complex salt of 5-aminolevulinic acid, N-acyl-5-aminolevulinic acid, salts of N-acyl-5-aminolevulinic acid and a complex ester of N-acyl-5-aminolevulinic acid, with a compound selected from iron citrate, iron (II)citrate sodium-ferric ammonium citrate iron, acetate jelly the and, the iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium-iron.

5. A means to prevent/reduce wrinkles and age spots, containing as active ingredients a compound of iron and a compound selected from 5-aminolevulinic acid, salts of 5-aminolevulinic acid, a complex ester of 5-aminolevulinic acid, ether complex salt of 5-aminolevulinic acid, N-acyl-5-aminolevulinic acid, salts of N-acyl-5-aminolevulinic acid and a complex ester of N-acyl-5-aminolevulinic acid, with a compound selected from iron citrate, iron (II)citrate sodium-ferric ammonium citrate iron, the iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium is elesa, ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium-iron.

6. The way to prevent/reduce agrability skin containing percutaneous insertion of external application to skin, which, as the active component contains a compound of iron and a compound selected from 5-aminolevulinic acid, salts of 5-aminolevulinic acid, a complex ester of 5-aminolevulinic acid, ether complex salt of 5-aminolevulinic acid, N-acyl-5-aminolevulinic acid, salts of N-acyl-5-aminolevulinic acid and a complex ester of N-acyl-5-aminolevulinic acid, with a compound selected from iron citrate, iron (II)citrate-ferric ammonium citrate iron, iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium-iron.

7. Methods for the prevention/reduction of dry skin, containing percutaneous insertion of external application to skin, which, as the active component contains a compound of iron and a compound selected from 5-aminolevulinic acid, salts of 5-aminolevulinic acid, a complex ester of 5-aminolevulinic acid, ether complex salt of 5-aminolevulinic acid, N-acyl-5-aminolevulinic acid, salts of N-acyl-5-aminolevulinic acid and a complex ester of N-acyl-5-aminolevulinic acid, with a compound selected from iron citrate, iron (II)citrate sodium-ferric ammonium citrate iron, the iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium-iron.

8. The way to prevent/reduce wrinkles/age spots containing percutaneous insertion of external application to skin, which, as the active component contains a compound of iron and a compound selected from 5-aminolevulinic acid, salts of 5-and inrevenue acid, complex ester of 5-aminolevulinic acid, ether complex salt of 5-aminolevulinic acid, N-acyl-5-aminolevulinic acid, salts of N-acyl-5-aminolevulinic acid and a complex ester of N-acyl-5-aminolevulinic acid, with a compound selected from iron citrate, iron (II)citrate sodium-ferric ammonium citrate iron, iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III)heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium-iron.

9. A means for improvement in atopic dermatitis, comprising as active ingredients a compound of iron and a compound selected from 5-aminolevulinic acid, salts of 5-aminolevulinic acid, a complex ester of 5-aminolevulinic acid, ether complex salt of 5-aminolevulinic acid, N-acyl-5-aminolevulinic acid, salts of N-acyl-5-aminolevulinic acid and a complex ester of N-acyl-5-aminolevulinic acid, with a compound selected from iron citrate, iron (II)citrate N. the Tria gland, ammonium citrate iron, iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium-iron.

10. The way of improvement in atopic dermatitis containing percutaneous insertion of external application to skin, which, as the active component contains a compound of iron and a compound selected from 5-aminolevulinic acid, salts of 5-aminolevulinic acid, a complex ester of 5-aminolevulinic acid, ether complex salt of 5-aminolevulinic acid, N-acyl-5-aminolevulinic acid, salts of N-acyl-5-aminolevulinic acid and a complex ester of N-acyl-5-aminolevulinic acid, with a compound selected from iron citrate, iron (II)citrate-ferric ammonium citrate iron, iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, sodium lactate jelly is a, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium-iron.

11. Means external application to skin, comprising a first agent which contains a compound selected from 5-aminolevulinic acid, salts of 5-aminolevulinic acid, a complex ester of 5-aminolevulinic acid, ether complex salt of 5-aminolevulinic acid, N-acyl-5-aminolevulinic acid, salts of N-acyl-5-aminolevulinic acid and a complex ester of N-acyl-5-aminolevulinic acid, and a second agent which contains a compound of iron and a compound selected from iron citrate, iron (II)citrate sodium-ferric citrate ammonium-iron, iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, decarboxylation marriageless and decarboxylation ammonium-iron, the first agent and second agent are separated and used in combination.

12. Means external application for skin according to claim 11, in which the first and/or second agent further comprises urea.

13. The way to prevent/reduce agrability skin containing the percutaneous introduction of a first agent which contains a compound selected from 5-aminolevulinic acid, salts of 5-aminolevulinic acid, a complex ester of 5-aminolevulinic acid, ether complex salt of 5-aminolevulinic acid, N-acyl-5-aminolevulinic acid, salts of N-acyl-5-aminolevulinic acid and a complex ester of N-acyl-5-aminolevulinic acid, and a second agent which contains a compound of iron and a compound selected from iron citrate, iron (II)citrate, iron, and ammonium citrate iron, iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium-iron.

14. The way to prevent/is menichini dry skin, containing the percutaneous introduction of a first agent which contains a compound selected from 5-aminolevulinic acid, salts of 5-aminolevulinic acid, a complex ester of 5-aminolevulinic acid, ether complex salt of 5-aminolevulinic acid, N-acyl-5-aminolevulinic acid, salts of N-acyl-5-aminolevulinic acid and a complex ester of N-acyl-5-aminolevulinic acid, and a second agent which contains a compound of iron and a compound selected from iron citrate, iron (II)citrate sodium-ferric ammonium citrate iron, iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium-iron.

15. The way to prevent/reduce wrinkles/age spots containing the percutaneous introduction of a first agent which contains a compound selected from 5-aminolevulinic acid, salts of 5-aminolevulinic acid, a complex ester of 5-aminolevulinic acid, ether complex salt of 5-aminolevulic the OIC acid, N-acyl-5-aminolevulinic acid, salts of N-acyl-5-aminolevulinic acid and a complex ester of N-acyl-5-aminolevulinic acid, and a second agent which contains a compound of iron and a compound selected from iron citrate, iron (II)citrate sodium-ferric ammonium citrate iron, iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium-iron.

16. The way of improvement in atopic dermatitis containing the percutaneous introduction of a first agent which contains a compound selected from 5-aminolevulinic acid, salts of 5-aminolevulinic acid, a complex ester of 5-aminolevulinic acid, ether complex salt of 5-aminolevulinic acid, N-acyl-5-aminolevulinic acid, salts of N-acyl-5-aminolevulinic acid and a complex ester of N-acyl-5-aminolevulinic acid, and a second agent which contains a compound of iron and a compound selected from iron citrate, iron (II), is itrate sodium-iron, ammonium citrate iron, iron acetate, iron oxalate, succinate of iron (II)succinate and citrate of sodium iron pyrophosphate of iron (II), pyrophosphate of iron (III), heme iron, iron dextran, iron lactate, gluconate iron (II), diethylenetriaminepentaacetate sodium-iron, diethylenetriaminepentaacetate ammonium ferric ethylenediaminetetraacetate sodium-iron, ethylenediaminetriacetate ammonium-iron, Triethylenetetramine iron, dicarboxylate sodium-iron and decarboxylation ammonium-iron.



 

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6 cl, 4 tbl, 16 ex

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula I or formula II, to their pharmaceutically acceptable salts, enantiomers and diastereoisomers as metalloprotease inhibitors, and also to a pharmaceutical composition based thereon and to versions of application thereof. Said compounds can find application in treatment of the diseases mediated by activity of metalloproteases, Her-2 SHEDDASE, ADAM-10 and ADAM-17, such as arthritis, cancer, cardiovascular disorders, skin diseases, inflammatory and allergic conditions, etc. In general formula I or II: A represents CWNHOH; B represents CH2; G represents CH2; D represents oxygen; X represents CH2NRb; Y represents CH2; M represents C; U is absent or represents NRb; V is absent or represents phenyl, or 4-10-members heterocyclyl containing 1-2 heteroatoms chosen from N and S, substituted with 0-5 groups Re; U' is absent or represents C1-10alkylene, O or combinations thereof; V' represents H, C1-8alkyl, NRbRc, C6-10carbocyclyl substituted with 0-3 groups Re, or 5-14-members heterocyclyl containing 1-3 heteroatoms chosen from N, O and C substituted with 0-4 groups Re; Ra and Re, independently represents H, T, C1-8alkylene-T, C(O)NRa'(CRb'Rc')r-T, (CRb'Rc')r-O-(CRb'Rc')r-T, OH, Cl, F, CN, NO2, NRIRII, COORIV, ORIV, CONRIRII, C1-8halogenalkyl, C3-13carbocyclyl; Rb and Rc independently represents H, T, C1-6alkylene-T, C(O)O(CRb'Rc')r-T, C(O)(CRb'Rc')r-T, S(O)p(CRb'Rc')r-T; T represents H, C1-10alkyl substituted with 0-1 groups Rb'; C3-6carbocyclyl, 5-6-members heterocyclyl containing one oxygen atom; Ra' Rb' and Rc' independently represents H, ORIV or phenyl; R1 represents hydrogen; R2 represents hydrogen; R3 represents: (i) C1-10alkyl; (ii) 4-14-members heterocyclyl containing 1-3 nitrogen atoms optionally substituted with one or two substitutes chosen from C1-6alkyl, OR13, 5-10-members heterocyclyl containing 1-3 heteroatoms chosen from N O and C, or phenyl; (iii) NR16R17; R4 represents H; R4' represents H; R5' represents H; W represents oxygen; R13 represents C1-C6alkyl; R16 and R17 independently represents C1-C10alkyl or phenyl where each is optionally substituted with one C1-4alkyl; RI and RIIindependently represents H or C1-6alkyl; RIV represents C1-6alkyl; i is equal to 0; p is equal to 1 or 2 and r is equal to 0, 1 or 2; provided that a) a spiro ring represents a stable chemical base unit and b) NR8 and NRb do not contain neither N-N, nor N-O bonds.

EFFECT: higher efficiency of the composition and method of treatment.

54 cl, 1 tbl, 9 dwg, 284 ex

FIELD: chemistry.

SUBSTANCE: proposed phosphodiesterase 4 inhibitors are characterised by formulae II, III, V, VI, where X is CH or N; L is a single bond, -(CH2)nCONH-, -(CH2)nCON(CH2CH3)-, (CH2)nSO2, (CH2)nCO2 or alkylene, optionally substituted oxo or hydroxy; n assumes values from 0 to 3; R1 is optionally substituted alkyl; R3 - H, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted phenyl, phenylalkyl, heterocyclyl, heterocyclylalkyl or cycloalkylalkyl; R4 and R5 represent alkyl; R6 - cycloalkyl, R7 is H; R8 is H, carboxy, alkoxycarbonyl, -CO-alkyl, optionally substituted alkyl.

EFFECT: new phosphodiesterase 4 inhibitors have improved properties.

55 cl, 30 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry, particularly a preparation that is able to suppress an immune response underlying immunoglobulin-E-dependent allergic diseases. Application of water-soluble polysaccharides made of clover (Trifolium pretense L.), as a preparation able to suppress the immune response underlying immunoglobulin-E- dependent allergic diseases.

EFFECT: polysaccharides made of clover (Trifolium pretense L) exhibit effective antiallergic activity and affect the earliest stages of formation of Th2-dependent allergic reactions associated with development of immunoglobulins E and G1.

3 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry and concerns pharmaceutical composition for prevention and treatment of diseases and disease states connected with metabolic pathways of cycloxygenase-2 (CG-2) and 5-lipooxygenase (5-LO), which contains mixture of extract obtained from Scutellariae and enriched with flavonoids with free B-ring, which include baicalein, and extract obtained from Acacia and enriched with flavans, which include catechine and epicatechine. Claimed invention also relates to method of body weight loss and control over glucose level in blood. Methods by claimed invention include introduction to person, who needs it, of efficient amount of composition by claimed invention together with pharmaceutically acceptable carrier. Claimed invention mainly relates to prevention and treatment of diseases and states connected with metabolic pathways of cycloxygenase-2 (CG-2) and 5-lipooxygenase (5-LO), including, but not confining to it, stopping discomfort and pain in joints, induced by such states as osteoarthritis, rheumatoid arthritis and other injuries caused by overload.

EFFECT: composition possesses high efficiency.

35 cl, 22 ex, 15 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel methods (versions) of producing N-acyl derivatives of amino acids of general formula , where n equals 2 or 3; and R is or their salts, using anhydrides of glutaric or succinic acid.

EFFECT: advantages of the proposed methods lie in simplicity of their realisation, easy extraction of the end product and high output of the end products.

2 cl, 27 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-H-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazole[3,4-b]pyridine-5-carboxamide, which is a compound of formula or its pharmaceutically acceptable salt, as well as to a method of producing said compounds. The invention also relates to use of the said compound or its pharmaceutically acceptable salt as phosphodiesterase IV (PDE4) inhibitor, for example in treatment and/or prevention of inflammatory and/or allergic disease, cognitive impairment or depression in mammals. The invention particularly pertains to use of the compound or its pharmaceutically acceptable salt in treating and/or preventing atopic dermatitis in mammals, for example via external local administration to a mammal, for example a human being.

EFFECT: pharmaceutical compositions are also provided, which contain the said compound or its pharmaceutically acceptable salt, particularly suitable for external local administration.

35 cl, 1 tbl, 19 ex

Antiallergic agent // 2378004

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry, particularly an agent able to inhibit immune response underlying immunoglobulin-E-dependent allergic diseases. Application of water-soluble polysaccharides made of Acorns calamus L. root, as an agent able to inhibit immune response underlying immunoglobulin-E-dependent allergic diseases.

EFFECT: said polysaccharides made of Acorns calamus L root are able to inhibit the first-stage development of immunoglobulin-E-dependent allergies that cause reduced synthesis of immunoglobulins classes E and G1 that ensures inhibition of further events related to development and release of biologically active substances taking a damaging action on cells and tissues.

3 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: new compounds of thienopyrazole are described with formula (1) , where R1 means non-substituted C3-C8-cycloalkyl group or tetrahydropyranyl, R2 means non-substituted C1-C3alkyl group, R3 means atom of hydrogen, R4 means various groups mentioned in invention formula. Compounds inhibit PDE 7 and, accordingly, increase cell level of cyclic adenosine monophosphate. Pharmaceutical composition is also described, as well as method for inhibition of PDE, methods for production of compound with formula (1), where R4 means CO2R7, and intermediate compounds.

EFFECT: possibility to use for treatment of various types of such diseases as allergic diseases, inflammatory diseases or immunological diseases.

20 cl, 138 tbl, 440 ex

FIELD: medicine.

SUBSTANCE: invention relates to a method of producing 2-amino-2-[2-[4-(3-benzyloxy-phenylthio)-2-chlorophenyl]ethyl]-1,3-propanediol hydrochloride or its hydrate, involving the following steps: reacting 4-(3-benzyloxyphenylthio)-2-chlorobenzaldehyde and diethylphosphonoacetate ethyl in a solvent in the presence of a base, obtaining ethyl 3-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]acrylate; reducing the formed ethyl 3-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]acrylate with subsequent mesylation, iodizing, and nitration, obtaining 1-benzyloxy-3-[3-chloro-4-(3-nitropropyl-phenylthio]benzol; hydroxymethylation of the formed 1-benzyloxy-3-[3-chloro-4-(3-nitropropyl-phenylthio] benzol with formaldehyde, obtaining 2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1,3-propanediol; as well as reduction of the formed 2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1,3-propanediol, obtaining the end product. The invention also relates to intermediate products: ethyl 3-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]acrylate, 1-benzyloxy-3-[3-chloro-4-(3-nitropropylphenylthio]benzol, 2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1,3-propanediol or to their hydrates.

EFFECT: industrial production of said compound with good output and high purity.

4 cl, 4 ex

FIELD: medicine.

SUBSTANCE: carboxylic acid compounds are presented by formula (I) where R1 represents (1) hydrogen atom, (2) C1-4alkyl; E represents -CO-; R2 represents (1) halogen atom, (2) C1-6 alkyl, (3) trihalogen methyl; R3 represents (1) halogen atom, (2) C1-6alkyl; R4 represents (1) hydrogen atom; R5 represents (1) C1-6alkyl; represents phenyl; G represents (1) C1-6alkylene; represents 9-12-merous bicyclic heterocycle containing heteroatoms, chosen of 1-4 nitrogen atoms, one or two oxygen atoms; m represents 0 or an integer 1 to 4, n represents 0 or an integer 1 to 4, and i represents 0 or an integer 1 to 11 where R2 can be identical or different provided m is equal to 2 or more, R3 can be identical or different provided n is equal to 2 or more, and R5 can be identical or different provided i is equal to 2 or more; both R12 and R13, independently represent (1) C1-4alkyl, (2) halogen atom, (3) hydroxyl or (4) hydrogen atom, or R12 and R13 together represent (1) oxo or (2) C2-5alkylene and where provided R12 and R13 simultaneously represent hydrogen atom, carboxylic acid compound presented by formula (I), represents a compound chosen from the group including the compounds (1) - (32), listed in cl.1 of the patent claim. Besides the invention concerns a pharmaceutical composition based in the compound of formula I and to application of the compound of formula I for making the pharmaceutical composition.

EFFECT: there are produced new carboxylic acid derivatives with antagonistic activity with respect to DP receptor.

14 cl, 74 ex

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