Skin texture improver

Abstract

The purpose of the present invention is to provide a safe, effective agent for improving skin texture. It was discovered that a pharmaceutical composition having a polysulfated mucopolysaccharide such as a heparinoid, etc., or a salt thereof as an active ingredient is useful for improving skin texture or shrinking a bumpy area.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition containing polysulfated mucopolysaccharides useful for improving skin markings. [Background technology]

[0002] The surface of human skin is not uniformly smooth, but has numerous fine grooves called skin sulci. Some of the skin sulci are deep, while others are shallow. A small protuberance surrounded by shallow skin sulci is called a skin mound. Several of these skin sulci are surrounded by deeper skin sulci to form a polygonal skin field. Hair grows from the deep skin sulci, and sweat pores of sweat glands open into the skin sulci (New Skin Science, Shimizu Hiroshi, Nakayama Shoten, 2011, pp. 2-3). The pattern created by these skin sulci and skin sulci is called skin pattern, or skin pattern. In general, the size of each skin sulcus (skin sulcus area) varies with age; the younger the person is, the smaller the skin sulcus area and the deeper the skin sulci; the older the person is, the larger the skin sulcus area and the shallower the skin sulci.

[0003] The state of the skin ridge and the skin groove is an index for evaluating the state of the skin surface. For example, a method for evaluating the skin condition by quantifying the average of the skin ridge area and the skin groove depth using enlarged images of the skin of each part to be compared (Patent Document 1: JP 2005-034424 A) and a method for evaluating the skin condition using the gloss density value and gloss area value from the skin groove image and the skin ridge image (Patent Document 2: JP 2014-087464 A) are known, and the size of the skin ridge area is an excellent index for quantifying and evaluating the skin condition.

[0004] The surface of the skin is easily affected by ultraviolet rays, dryness, inflammation, etc., and the shape of the skin ridges and skin grooves becomes distorted and the condition of the skin pattern worsens as the skin ridges become larger and the skin grooves become shallower. In skin diseases such as atopic dermatitis, the barrier function of the skin becomes abnormal and dry skin tends to become more severe, so there is a problem that even if treatment for atopic dermatitis is administered, the condition of the skin surface does not improve. Topical steroid preparations are used to treat atopic dermatitis, but these are intended to suppress inflammatory symptoms and do not improve skin conditions such as dryness. Vaseline is often used to treat atopic dermatitis, eczema, and dry skin to prevent moisture loss from the skin or to protect the skin, but its effect in improving skin markings is unknown. Heparinoids are known as polysulfated chondroitin sulfates, which are polysulfated mucopolysaccharides and are listed in the Japanese Pharmacopoeia's Standards for Pharmaceutical Ingredients, and have been recognized to be effective in the treatment and prevention of thrombophlebitis (including hemorrhoids), pain and inflammatory diseases due to circulatory disorders (induration and pain after injections), chilblains, hypertrophic scars and keloids, progressive keratoderma tylodes palmaris, asteatosis, swelling, hematoma, tenosynovitis, muscle pain, arthritis after trauma (bruises, sprains, contusions), and muscular torticollis (infancy) (Non-patent literature 1: Package insert for Hirudoid Lotion 0.3%, revised September 2017). Polysulfated chondroitin sulfate is also known to be used as a therapeutic agent for psoriasis (Patent Document 3: JP 09-286731 A), a therapeutic agent for chronic prurigo (Patent Document 4: JP 2013-018709 A), and a barrier function recovery promoter (Patent Document 5: JP 2009-013134 A). However, it has not been known until now that polysulfated mucopolysaccharides such as polysulfated chondroitin sulfate can improve skin markings. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent Publication No. 2005-034424 [Patent Document 2] Patent Publication No. 2014-087464 [Patent Document 3] Patent Publication No. 09-286731 [Patent Document 4] Patent Publication No. 2013-018709 [Patent Document 5] Patent Publication No. 2009-013134 [Non-patent literature]

[0006] [Non-Patent Document 1] Hirudoid Lotion 0.3% September 2017 revised package insert DISCLOSURE OF THEINVENTION [Problem to be solved by the invention]

[0007] The present invention provides a pharmaceutical composition for use in reducing the cutaneous tumour area. [Means for solving the problem]

[0008] As a result of extensive research, the inventors discovered that a heparinoid, a polysulfated mucopolysaccharide, improves skin markings by regulating the shape of skin ridges and skin grooves and reducing the area of ​​skin ridges, thereby completing the present invention.

[0009] That is, the present invention is as follows. (1) A skin marking improving agent comprising a polysulfated mucopolysaccharide or a salt thereof. (2) The skin pattern improving agent according to (1), wherein the polysulfated mucopolysaccharide is polysulfated chondroitin sulfate. (3) The skin pattern improving agent according to (2), wherein the polysulfated chondroitin sulfate is a heparinoid. (4) The skin marking improving agent according to any one of (1) to (3), which is an external preparation. (5) A pharmaceutical composition comprising a polysulfated mucopolysaccharide or a salt thereof for use in reducing the area of ​​a cutaneous ridge. (6) The pharmaceutical composition according to (5), wherein the polysulfated mucopolysaccharide is polysulfated chondroitin sulfate. (7) The pharmaceutical composition according to (6), wherein the polysulfated chondroitin sulfate is a heparinoid. (8) An external preparation comprising the pharmaceutical composition according to any one of (5) to (7). (9) A method for improving skin markings, which comprises applying a polysulfated mucopolysaccharide or a salt thereof to the skin. (10) The method according to (9), wherein the polysulfated mucopolysaccharide is polysulfated chondroitin sulfate. (11) The method according to (10), wherein the polysulfated chondroitin sulfate is a heparin-like substance. (12) The polysulfated mucopolysaccharide or a salt thereof is administered in an amount of 1 cm per dose. 2 The method according to any one of (9) to (11), wherein the amount of the applied layer is 0.5 mg to 2 mg per unit area. (13) A method for reducing a keratinocyte area of ​​skin, which comprises applying a polysulfated mucopolysaccharide or a salt thereof to the skin. (14) The method according to (13), wherein the polysulfated mucopolysaccharide is polysulfated chondroitin sulfate. (15) The method according to (14), wherein the polysulfated chondroitin sulfate is a heparin-like substance. (16) The polysulfated mucopolysaccharide or a salt thereof is administered in an amount of 1 cm per dose. 2 The method according to any one of (13) to (15), wherein the amount of the applied agent is 0.5 mg to 2 mg per dose. Effect of the Invention

[0010] Polysulfated mucopolysaccharides such as heparinoids are useful as agents for adjusting the shape of the skin ridges and skin grooves and reducing the area of ​​the skin ridges. [Brief description of the drawings]

[0011] [Figure 1] A comparison of the average skin mound area after applying Hirudoid cream (2mg / cm2, 6mg / cm2) and white petrolatum (2mg / cm2) twice daily for 7 days is shown (n=1). [Diagram 2] The average skin mound area after applying Hirudoid cream (2mg / cm2, 6mg / cm2) and white petrolatum (2mg / cm2) twice daily for 7 days is compared (n=7). [Diagram 3] The frequency distribution by skin mound area is shown below after no application (before application), application of Hirudoid cream (2mg / cm2, 6mg / cm2), and application of white petrolatum (2mg / cm2) twice daily for 7 days. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The present invention will be described in detail below. The term "polysulfated mucopolysaccharide" refers to a long-chain polysaccharide having a repeating unit of a disaccharide consisting of hexosamine and uronic acid or galactose, which has been sulfated. Some naturally occurring mucopolysaccharides have sulfate groups in the sugar chain, and therefore these and those which have been further chemically sulfated are also included in the polysulfated mucopolysaccharides of the present invention.

[0013] The term "hexosamine" broadly refers to a compound in which the hydroxyl group of a hexose is substituted with an amino group, and specific examples include D-glucosamine, D-galactosamine, etc. The amino group of the hexosamine may be substituted with an acetyl group.

[0014] Furthermore, the term "uronic acid" broadly refers to a compound in which the primary alcohol of an aldose is oxidized to a carboxyl group, and specific examples of such naturally occurring uronic acids include D-glucuronic acid, L-iduronic acid, D-galacturonic acid, D-mannuronic acid, and L-guluronic acid.

[0015] As the polysulfated mucopolysaccharide, a polysaccharide having a repeating unit of a disaccharide consisting of D-acetylgalactosamine and uronic acid or galactose is preferably polysulfated, and specific examples thereof include polysulfated chondroitin sulfate, polysulfated dermatan sulfate, etc., with polysulfated chondroitin sulfate being more preferred.

[0016] The number of sulfate groups in the polysulfated mucopolysaccharide of the present invention is not particularly limited, but is usually 0.55 to 4 molecules on average, preferably 0.6 to 2.9 molecules on average, and more preferably 0.7 to 2 molecules on average, per monosaccharide.

[0017] The molecular weight of the polysulfated mucopolysaccharide or its salt used in the present invention varies depending on the type of polysaccharide and is not limited, but the average molecular weight is about 10,000 to 10,000,000 in weight average molecular weight, and preferably about 10,000 to 50,000. In addition, the weight average molecular weight used in this specification is calculated by the following formula when Ni polymers each having a molecular weight of Mi are present: Weight average molecular weight (Mw)=Σ(Ni·Mi 2 ) / Σ(Ni·Mi) It is a value expressed as:

[0018] The polysulfated mucopolysaccharide of the present invention is not particularly limited in terms of origin, but more preferred examples include those obtained by artificially subjecting the above-mentioned naturally occurring mucopolysaccharides to a sulfation treatment.

[0019] Methods for introducing sulfate groups into mucopolysaccharides such as chondroitin sulfate include known methods, such as a method of heating mucopolysaccharides and a sulfating agent in a suitable solvent to cause them to react. The sulfating agent is not particularly limited as long as it can achieve the purpose of polysulfation, but it is preferable to use a complex of sulfuric anhydride and pyridine or triethylamine. The ratio of mucopolysaccharide to sulfating agent used can be selected arbitrarily according to the desired sulfation rate (or sulfur content) of sulfated mucopolysaccharide and reaction conditions, but is generally used in a ratio of 2 to 10 parts by weight per 1 part by weight of mucopolysaccharide. Examples of solvents include protophilic solvents such as dimethylformamide. The reaction temperature and reaction time are not particularly limited as long as the desired sulfation rate can be achieved, but for example, the reaction is carried out at 40 to 90°C for about 30 minutes to 20 days.

[0020] The polysulfated mucopolysaccharides produced as described above can be purified by purification procedures commonly used for various modified polysaccharides, such as neutralization, desalting by dialysis, recovery of precipitates by addition of an organic solvent, and recovery by freeze-drying.

[0021] In the present invention, the polysulfated mucopolysaccharide may be used in the form of a physiologically acceptable salt. Examples of physiologically acceptable salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, and magnesium salts, and also include multiple salts of these.

[0022] "Polysulfated chondroitin sulfate" is a polymer containing about 2 to 4, and preferably about 2 to 3, sulfate ester residues per disaccharide unit consisting of D-acetylgalactosamine and D-glucuronic acid.

[0023] Polysulfated chondroitin sulfate can be easily produced by a known method in which a chondroitin component such as chondroitin or chondroitin sulfate (A, C, D, E) is reacted with a sulfating agent such as chlorosulfuric acid, concentrated sulfuric acid, or sulfur trioxide-pyridine complex.

[0024] Preferred examples of polysulfated chondroitin sulfate include heparinoids listed in the Japanese Pharmacopoeia Non-Drug Ingredients Standards. Specifically, it is a polysulfated chondroitin sulfate exhibiting the following physicochemical properties: a) Sulfate group content: 25.8~37.3% b) Intrinsic viscosity: 0.09~0.18

[0025] Polysulfated chondroitin sulfate may be used in the form of a free acid derived from the sulfate residues, but is usually used in the form of a base salt.

[0026] Examples of the base salt include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium, and magnesium salts.

[0027] A "skin mound" refers to a small protuberance on the surface of the skin, surrounded by fine shallow grooves (skin grooves). "Skin grooves" refer to the fine grooves on the surface of the skin. "Skin markings" generally refer to patterns formed by skin grooves and ridges, but in the present invention refers to skin marks on the palms and soles of the feet other than the skin marks (so-called fingerprints and palm prints). "Improvement of skin markings" refers to the area of ​​the skin ridges that make up the skin markings becoming smaller compared to before treatment, and the skin markings becoming denser. "Dense skin markings" refers to the number of skin ridges in a certain area of ​​the skin markings increasing after treatment compared to the number of skin ridges in the same area before treatment, i.e., the area of ​​each skin ridge decreasing. By improving the skin markings, the stratum corneum moisture content, barrier function, etc. are restored to normal. "Skin ridge area" refers to the area of ​​each skin ridge that constitutes the skin pattern or its average value. The skin ridge area can be measured by known methods such as a method of calculating the area by image analysis using a skin image (Fukuoka Medical Journal 94(5):108-109, 2003) or the impression mold method (Clin Auto Res (2002) 12:20-23). "Reduction in skin ridge area" refers to a significant decrease in the area per skin ridge or its average area compared to before treatment.

[0028] According to the present invention, it is possible to provide a pharmaceutical composition which contains the above-mentioned polysulfated mucopolysaccharide as an active ingredient and is effective in improving skin markings.

[0029] The content of polysulfated mucopolysaccharide in the pharmaceutical composition of the present invention is not particularly limited, and may be, for example, 0.01 to 5 wt%, preferably 0.05 to 3 wt%, more preferably 0.1 to 1 wt%, particularly preferably 0.1 to 0.5 wt%, and most preferably 0.1 to 0.3 wt%.

[0030] The pharmaceutical composition of the present invention can be used as an external preparation, specifically in the form of an ointment, plaster, patch, cream, lotion, emulsion lotion, gel, foam, etc. Furthermore, in the case of a form in which an aqueous phase and an oil phase are emulsified, such as a cream or an emulsion lotion (emulsion composition), the emulsion may be in any emulsion form, such as oil-in-water (O / W) type, water-in-oil (W / O) type, water-in-oil-in-water (W / O / W) type, or oil-in-water-in-oil (O / W / O) type. The pharmaceutical composition of the present invention can be prepared by a commonly used method using additives commonly used in the art, i.e., pharmaceutical excipients and pharmaceutical carriers such as those shown below.

[0031] Additives to be incorporated into ointments include bases, moisturizers, thickeners, emulsifiers, etc. As bases, higher hydrocarbons, oils and fats, waxes, fatty acids, higher alcohols, fatty acid esters, etc. can be used.

[0032] Examples of moisturizing agents include glycerin, 1,3-butylene glycol, etc. Examples of thickening agents include carboxyvinyl polymer, carboxymethylcellulose, etc. Examples of emulsifying agents include cationic surfactants, anionic surfactants, amphoteric surfactants, nonionic surfactants, etc.

[0033] Additives to be incorporated into the plaster or patch include thickeners, moisturizers, fillers, crosslinkers, solubilizers, emulsifiers, etc. Examples of thickeners include sodium alginate, gelatin, methylcellulose, carboxyvinyl polymer, sodium polyacrylate, etc. Examples of moisturizers include glycerin, etc. Examples of fillers include kaolin, titanium dioxide, zinc oxide, etc. Examples of crosslinkers include acetaldehyde, dimethyl ketone, aluminum sulfate, etc. Examples of solubilizers include alcohols such as ethanol and isopropanol, etc. Examples of emulsifiers include anionic surfactants, nonionic surfactants, etc.

[0034] Additives that can be incorporated into creams include oil-soluble substances, water-soluble substances, emulsifiers, and the like. As the oil-soluble substance, higher hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, fatty acid esters, etc. can be used. Examples of the water-soluble substance include water, a dissolving agent, a thickening agent, and a moisturizing agent. Examples of the dissolving agent include lower alcohols such as ethanol, propanol, and isopropanol. Examples of the thickening agent include carboxyvinyl polymer and carboxymethylcellulose. Examples of the moisturizing agent include glycerin, propylene glycol, and 1,3-butylene glycol. The emulsifier includes cationic surfactants, anionic surfactants, amphoteric surfactants, nonionic surfactants, and the like.

[0035] Additives that can be incorporated into lotions and emulsion-type lotions include oil-soluble substances, water-soluble substances, moisturizers, emulsifiers, and the like. As the oil-soluble substance, higher hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, fatty acid esters, etc. can be used. Examples of the water-soluble substance that can be used include water, a thickening agent, a moisturizing agent, etc. Examples of the thickening agent include carboxyvinyl polymer, carboxymethylcellulose, etc. Examples of the moisturizing agent include glycerin, 1,3-butylene glycol, etc. The emulsifier includes cationic surfactants, anionic surfactants, amphoteric surfactants, nonionic surfactants, and the like.

[0036] Additives to be incorporated into the gel include bases, thickeners, etc. Examples of bases include isopropanol, propylene glycol, etc. Examples of thickeners include carboxyvinyl polymers, carboxymethylcellulose, etc.

[0037] Additives to be incorporated into the foam agent include a base agent, a foaming agent, and the like. Examples of bases include water, glycerin, 1,3-butylene glycol, dipropylene glycol, propylene glycol, D-sorbitol, polyethylene glycol, 2-ethylhexanediol, isostearyl alcohol, octyldodecanol, hexyldecanol, oleyl alcohol, isostearic acid, oleic acid, oleyl oleate, isopropyl myristate, octyldodecyl myristate, glycerin triisooctanoate, cetyl 2-ethylhexanoate, isostearyl palmitate, medium-chain fatty acid triglyceride, castor oil, olive oil, triacetin, squalane, light liquid paraffin, liquid paraffin, squalene, white petrolatum, and gelling hydrocarbons. Examples of foaming agents include polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene polyoxypropylene glycol, glyceryl stearate, polyoxyethylene hydrogenated castor oil, decaglyceryl trioleate, polyoxyethylene cetyl ether, polyoxyethylene sorbit tetraoleate, sucrose stearate, polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene sorbit beeswax, polyoxyethylene glyceryl monostearate, polyoxyethylene lauryl ether, self-emulsifying glycerin monostearate, polyoxyethylene sorbitan monooleate, decaglyceryl monooleate, decaglyceryl monostearate, polyethylene glycol monostearate, polyoxyethylene behenyl ether, polyoxyethylene sorbitan laurate, sucrose laurate, polyoxyethylene sorbitan ... Examples of such an acid ester include uric acid ester, polyoxyethylene stearyl ether, sodium laurate, potassium palmitate, arginine stearate, sodium lauryl sulfate, potassium lauryl sulfate, sodium cetyl sulfate, polyoxyethylene triethanolamine lauryl sulfate, sodium lauroyl sarcosine, sodium N-stearoyl-N-methyl taurine, sodium N-myristoyl-N-methyl taurine, sodium monostearyl phosphate, sodium polyoxyethylene oleyl ether phosphate, sodium polyoxyethylene stearyl ether phosphate, sodium polyoxyethylene cetyl ether phosphate, sodium di-2-ethylhexyl sulfosuccinate, monosodium N-lauroyl glutamate, sodium N-stearoyl-L-glutamate, arginine N-stearoyl-L-glutamate, and sodium N-myristoyl-L-glutamate.

[0038] Examples of higher hydrocarbons that can be used in the above-mentioned preparations in the present invention include squalane, synthetic paraffin, liquid paraffin, white petrolatum, microcrystalline wax, etc. Examples of fats and oils that can be used in the above-mentioned preparations in the present invention include olive oil, jojoba oil, sesame oil, soybean oil, cacao butter, camellia oil, peanut oil, beef tallow, lard, triacetin, hardened oil, etc. Examples of waxes that can be used in the above-mentioned preparations in the present invention include beeswax, white beeswax, lanolin, ceresin wax, etc. Examples of fatty acids that can be used in the above-mentioned preparations in the present invention include stearic acid, oleic acid, etc. Examples of higher alcohols that can be used in the above-mentioned preparations in the present invention include lanolin alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, cholesterol, etc. Examples of fatty acid esters that can be used in the above-mentioned preparations in the present invention include isopropyl myristate, stearyl myristate, medium-chain fatty acid triglycerides, etc.

[0039] In the present invention, examples of the cationic surfactant that can be used in each of the above preparations include cetyltrimethylammonium chloride, lauryldimethylbenzylammonium chloride, tetrabutylammonium chloride, dioctadecyldimethylammonium chloride, and the like.

[0040] In the present invention, examples of the anionic surfactant include sodium alkylbenzene sulfonate, sodium dodecyl sulfate, sodium coconut alcohol ethoxy sulfate, sodium α-olefin sulfonate, emulsified cetostearyl alcohol, and the like.

[0041] In the present invention, examples of the nonionic surfactant include polyoxyethylene alkyl ether, polyoxyethylene alkylphenol ether, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, glycerin fatty acid ester, and diglycerin fatty acid ester.

[0042] In the present invention, examples of the amphoteric surfactant include N-alkyl-N,N-dimethylammonium betaine, imidazoline-type amphoteric surfactant, and the like.

[0043] The above surfactants can be used alone or in combination.

[0044] In the above-mentioned dosage forms such as ointments, plasters, patches, creams, lotions, emulsion lotions, gels, and foams, pH regulators, preservatives, macrogols, etc. may be used as necessary.

[0045] Examples of pH regulators include diisopropanolamine, triisopropanolamine, triethanolamine, L-arginine, potassium hydroxide, sodium hydroxide, sodium lactate, sodium citrate, phosphoric acid, tartaric acid, dl-malic acid, lactic acid, citric acid, glacial acetic acid, potassium dihydrogen phosphate glacial acetic acid, sodium edetate, etc. Examples of preservatives include thymol, dibutylhydroxytoluene, sodium edetate hydrate, phenoxyethanol, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, etc.

[0046] The dosage and administration of the pharmaceutical composition of the present invention varies depending on the age, weight, sex, and degree of skin condition (severe or mild) of the patient, and is not particularly limited. The pharmaceutical composition of the present invention is applied to the skin once to several times per day, preferably once to six times, more preferably once to three times, and even more preferably twice a day. The pharmaceutical composition of the present invention is administered in a concentration of 0.1 mg / cm 2 ~180mg / cm 2 In the pharmaceutical composition of the present invention, the polysulfated mucopolysaccharide or a salt thereof is applied in an amount of 1 cm per application. 2 The amount of the applied agent is 0.5 mg to 2 mg, preferably 0.6 mg to 1.8 mg, per one application. EXAMPLES

[0047] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0048] [Example 1] Four application sites were set on the forearm of one patient with atopic dermatitis. The test preparation was an oil-in-water cream containing polysulfated chondroitin sulfate (Hirudoid (registered trademark) cream 0.3%; hereafter simply referred to as Hirudoid cream or HC) and white petrolatum (moisturizer). The amount of Hirudoid cream applied at one time was 2 mg / cm, which is the standard amount of application for topical agents. 2 or three times that amount, 6 mg / cm 2 The amount of white petrolatum applied at one time is 2mg / cm, which is the standard amount of topical agents to be applied. 2 The above prescribed amount was applied twice a day (in the morning and after bathing in the evening) for 7 days. Before application of the test preparation and the day after the 7th day of application (before the morning application of the 8th day of application), the skin pattern was observed using the impression mold technique (IMT) described in Clin Auto Res (2002) 12:20-23, and the average skin mound area was calculated.

[0049] Hirudoid Cream contains 3.0 mg of polysulfated chondroitin sulfate (heparinoid) per 1 g of the formulation as an active ingredient. Other additives are glycerin, stearic acid, potassium hydroxide, white petrolatum, lanolin alcohol, cetostearyl alcohol, cetostearyl alcohol-sodium cetostearyl sulfate mixture, myristyl alcohol, methyl parahydroxybenzoate, propyl parahydroxybenzoate, isopropanol, and water.

[0050] The results are shown in Table 1 and Figure 1. In the areas where Hirudoid Cream was applied, the area per skin mound decreased 7 days after application compared to before application, and improvement in skin markings was observed. On the other hand, no improvement in skin markings was observed with white petrolatum (referred to as petrolatum in the tables and figures; the same applies below).

[0051] [Table 1]

[0052] During the clinical study period, no side effects were observed due to application of Hirudoid cream or white petrolatum.

[0053] [Example 2] The same test as in Example 1 was carried out on seven patients with atopic dermatitis. The results are shown in Table 2 and Figure 2. The area where Hirudoid cream was applied showed a clearer improvement in skin markings than the area where white petrolatum was applied.

[0054] [Table 2]

[0055] The frequency distribution by skin ridge area is shown in Figure 3. It was found that the area where Hirudoid cream was applied increased the number of small skin ridges compared to when no cream was applied or when white petrolatum was applied. Furthermore, no side effects were observed when applying Hirudoid cream or white petrolatum during this clinical study. [Industrial Applicability]

[0056] Heparinoids have been shown to have a significant effect in reducing the area of ​​skin ridges compared with no application or other drugs, and are therefore useful for improving skin markings or reducing the area of ​​skin ridges.

Claims

1. An agent for improving skin markings in patients with atopic dermatitis, comprising only a heparinoid or its salt as an active ingredient.

2. The skin marking improving agent according to claim 1 , which is an external preparation.

3. A pharmaceutical composition containing as an active ingredient only a heparinoid or its salt, which is used to reduce the area of ​​cutaneous ridges in patients with atopic dermatitis.

4. An external preparation comprising the pharmaceutical composition according to claim 3.

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