Skin preparations

Abstract

To provide an agent for improving degraded sweat gland functions.SOLUTION: The present invention provides an agent for improving degraded sweat gland functions, containing oversulfated chondroitin sulfate and / or a salt thereof as an active ingredient.SELECTED DRAWING: Figure 4

Description

[Technical field]

[0001] The present invention relates to an agent for improving reduced sweat gland function. [Background technology]

[0002] Sweat is a liquid secreted from sweat pores through sweat glands, and is involved in regulating body temperature and moisturizing the skin. Sweat glands consist of a secretory part and an excretory duct (sweat duct), and the secretory part is made up of secretory cells and myoepithelial cells. Myoepithelial cells are smooth muscles that contract to push sweat secreted from the secretory cells and stored in the lumen into the excretory duct, thereby sending the sweat to the skin surface. It has been reported that when the function of myoepithelial cells declines with age, the secretory part expands (i.e. the lumen of the sweat gland expands), and sweat production decreases.

[0003] A decrease in sweat gland function leads to a decrease in thermoregulation function or a decrease in the skin's moisture retention function. A decrease in thermoregulation function makes the person more susceptible to heat stroke, and a decrease in the skin's moisture retention function leads to dry skin, which induces itching and reduces the skin barrier function, making the person more susceptible to inflammatory skin diseases. As such, a decrease in sweat gland function can lead to various diseases, so improving decreased sweat gland function is important for human health.

[0004] Patent Document 1 discloses a skin preparation for external use to promote insensible sweating, which is important for moisturizing the skin. Non-Patent Documents 1 and 2 suggest that lichen amyloidosis and prurigo are associated with sweating disorders, respectively, and that such diseases can be alleviated by improving sweating disorders. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO2018 / 230733 [Non-patent literature]

[0006] [Non-Patent Document 1] British Journal of Dermatology (2017) 176, 1308-1315 [Non-Patent Document 2] Archives of Dermatological Research (2019) 311, 555-562 Summary of the Invention [Problem to be solved by the invention]

[0007] Although research has been reported on preventing / treating skin diseases by promoting sweating in this way, many aspects of sweat gland function remain unclear. Under these circumstances, an objective of the present invention is to provide an agent for improving reduced sweat gland function. [Means for solving the problem]

[0008] As a result of extensive research to solve the above problems, the inventors discovered that polysulfated chondroitin sulfate or a salt thereof reduces the lumen of sweat glands that has expanded due to aging, etc., thereby improving reduced sweat gland function and leading to the recovery of sweating, and thus completed the present invention.

[0009] That is, the present invention relates to an agent for improving reduced sweat gland function, which comprises polysulfated chondroitin sulfate and / or a salt thereof as an active ingredient.

[0010] The above-mentioned sweat gland function improving agent is suitable for improving sweat gland function that has been reduced by a drug.

[0011] The sweat gland function improver is also suitable for improving sweat gland function that has decreased with age.

[0012] The sweat gland function improving agent is also suitable for improving sweat gland function that has been reduced by dilating the sweat gland lumen. [Brief description of the drawings]

[0013] [Figure 1] 1 shows images showing histopathological findings of the footpad skin of young and old mice. [Diagram 2] These are images showing the pathological tissue of the footpad skin of mice repeatedly administered the corticosteroid clobetasol propionate (CP) and mice not administered CP (occlusion treatment only). [Diagram 3] These are images showing the pathological tissue of the footpad skin of mice that received repeated CP administration followed by application of a heparinoid substance (MPS) (CP+MPS) and mice that received only occlusion treatment followed by repeated CP administration (CP+occlusion treatment). [Figure 4] Graphs showing the ratio of lumen area to total sweat gland area, where (A) shows a comparison between young and old mice, and (B) shows changes due to CP administration and subsequent treatments. [Diagram 5] 13 is a graph showing the number of sweat droplets, in which (A) shows a comparison between young and old mice, and (B) shows the effect of MPS administration on old mice that were only subjected to occlusion treatment. [Figure 6] 1 is a graph showing the number of sweat droplets, where (A) shows the effect of repeated administration of CP, and (B) shows the number of sweat droplets increased by treatment performed after repeated administration of CP. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The sweat gland function improving agent of the present invention contains polysulfated chondroitin sulfate and / or a salt thereof as an active ingredient. Polysulfated chondroitin sulfate is a polymer that contains a disaccharide consisting of N-acetyl-D-galactosamine and D-glucuronic acid as a repeating unit, and contains about 2 to 4, and preferably about 2 to 3, sulfate ester residues per unit (disaccharide).

[0015] Polysulfated chondroitin sulfate can be easily produced by a known method of reacting a chondroitin component such as chondroitin or chondroitin sulfate (A, C, D, E) with a sulfating agent such as chlorosulfuric acid, concentrated sulfuric acid, sulfur trioxide-pyridine complex, etc. Chondroitin sulfate A has a sulfate ester residue at the 4th position of acetylgalactosamine, chondroitin sulfate C has a sulfate ester residue at the 6th position of acetylgalactosamine, chondroitin sulfate D has a sulfate ester residue at the 6th position of acetylgalactosamine and the 2nd or 3rd position of glucuronic acid, and chondroitin sulfate E has a sulfate ester residue at both the 4th and 6th positions of acetylgalactosamine.

[0016] A preferred example of the polysulfated chondroitin sulfate is a heparinoid listed in the Japanese Pharmacopoeia's Pharmaceutical Ingredients Standards. Specifically, it is a polysulfated chondroitin sulfate exhibiting the following physicochemical properties: a) Sulfate group content: 25.8~37.3% by weight b) Intrinsic viscosity: 0.09~0.18

[0017] 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.

[0018] Examples of the base salt include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium, and magnesium salts.

[0019] The weight average molecular weight of the polysulfated chondroitin sulfate or a salt thereof used in the present invention is not particularly limited, but is usually about 8,000 to 10,000,000, preferably about 8,000 to 1,000,000, more preferably about 10,000 to 100,000, and particularly preferably about 10,000 to 50,000.

[0020] The content of the active ingredient polysulfated chondroitin sulfate and / or a salt thereof is preferably 0.01 to 10% by weight, more preferably 0.05 to 5% by weight, and particularly preferably 0.1 to 1.0% by weight, based on the total weight of the sweat gland function improver (however, when the sweat gland function improver is composed of a concentrate and a propellant, the content is based on the total weight of the concentrate).Since polysulfated chondroitin sulfate is highly safe, when it is applied to the skin, it hardly causes side effects at the above concentration.

[0021] It has been reported that the lumen of sweat glands expands with age, and the amount of sweating decreases. The inventors have also found that repeated administration of corticosteroids (hereinafter, steroids) similarly expands the lumen of sweat glands and reduces the amount of sweating. Furthermore, the inventors have found that when polysulfated chondroitin sulfate or a salt thereof is applied to skin with an expanded lumen of sweat glands, the lumen of sweat glands shrinks and is restored to a normal state or a state close to normal, and as a result, the amount of sweating is restored. When the function of myoepithelial cells is reduced, the secretory part becomes more likely to expand (the lumen of sweat glands expands), and the contractile function of myoepithelial cells is reduced, which weakens the force that pushes sweat stored in the lumen from the duct to the skin surface, and therefore sweating is reduced. Although it is not intended to be bound by any theory, the present invention is believed to improve the function of reduced myoepithelial cells, reduce the expanded lumen of sweat glands, and increase the contractile force of myoepithelial cells to restore reduced sweat gland function.

[0022] The present invention can be used to prevent and / or treat conditions and / or diseases caused by decreased sweat gland function. Such conditions and diseases include heat stroke caused by decreased thermoregulatory function and inflammatory skin diseases caused by decreased moisturizing function. In particular, the elderly are less sensitive to heat and cold, so that the decrease in sweat gland function due to aging is likely to lead to heat stroke. Therefore, according to the present invention, the effect of preventing heat stroke can be expected through the recovery of thermoregulatory function by improving sweat gland function. Polysulfated chondroitin sulfate or a salt thereof has long been used in medical settings as a skin external preparation, and its safety in long-term administration has been established, so it is suitable for continuous use.

[0023] The sweat gland function improving agent of the present invention is particularly preferably for application to the skin, and can be used as a pharmaceutical composition or cosmetic composition. Examples of pharmaceutical compositions include compositions that fall under the category of medical drugs, prescription drugs, over-the-counter drugs, or quasi-drugs as defined in the Act on Ensuring Quality, Efficacy, and Safety of Pharmaceuticals, Medical Devices, etc. Examples of the cosmetic composition include cosmetics as defined in the "Law for Ensuring Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, etc." and compositions that fall under the category of quasi-drugs, i.e. medicated cosmetics.

[0024] The dosage form is not particularly limited as long as it is a form that can be applied to the skin, and examples of the dosage form include ointments, creams, gels, lotions, sprays (including foams), patches, etc. described in the Japanese Pharmacopoeia, and the composition can be used as a pharmaceutical composition or cosmetic composition together with pharmaceutically acceptable additives.

[0025] Examples of the additives include, but are not limited to, bases, surfactants, preservatives, pH adjusters, thickeners, and the like.

[0026] Examples of bases include, but are not limited to, higher hydrocarbons such as white petrolatum, squalane, and light liquid paraffin; waxes such as white beeswax, lanolin, and ceresin wax; fats and oils such as olive oil, jojoba oil, triacetin, and hydrogenated castor oil; higher alcohols such as lanolin alcohol, cetanol, myristyl alcohol, stearyl alcohol, and cetostearyl alcohol; fatty acids such as stearic acid; esters such as isopropyl myristate, stearyl myristate, and medium-chain fatty acid triglycerides; polyhydric alcohols such as glycerin and 1,3-butylene glycol; lower monohydric alcohols such as ethanol and isopropanol; water (purified water); macrogol (polyethylene glycol); silicone oil; and the like. Only one type or multiple types may be used.

[0027] Examples of surfactants (including those used as emulsifiers and foaming agents) include, but are not limited to, cationic surfactants, anionic surfactants, nonionic surfactants, and amphoteric surfactants, and may be used alone or in combination. Examples of cationic surfactants include, but are not limited to, cetyltrimethylammonium chloride, lauryldimethylbenzylammonium chloride, tetrabutylammonium chloride, and dioctadecyldimethylammonium chloride. Examples of anionic surfactants include, but are not limited to, sodium alkylbenzenesulfonate, sodium dodecyl sulfate, sodium coconut alcohol ethoxy sulfate, sodium α-olefinsulfonate, and emulsified cetostearyl alcohol (a mixture of cetostearyl alcohol and sodium cetostearyl sulfate). Examples of nonionic surfactants include, but are not limited to, glycerin fatty acid esters such as glyceryl monostearate, polyoxyethylene alkyl ethers such as polyoxyethylene cetyl ether and polyoxyethylene behenyl ether, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monostearate and polyoxyethylene sorbitan tristearate, etc. Examples of amphoteric surfactants include, but are not limited to, N-alkyl-N,N-dimethylammonium betaine, imidazoline-type amphoteric surfactants, etc.

[0028] Examples of preservatives include, but are not limited to, dibutylhydroxytoluene, sodium edetate hydrate, and paraoxybenzoic acid esters, and one or more of these may be used.

[0029] Examples of the pH adjuster include, but are not limited to, diisopropanolamine, triisopropanolamine, triethanolamine, potassium hydroxide, sodium hydroxide, and the like, and one or more kinds may be used.

[0030] Examples of the thickening agent include, but are not limited to, sodium alginate, gelatin, carboxyvinyl polymer, and carboxymethylcellulose, and one or more kinds may be used.

[0031] In addition, when the dosage form is a foam, a propellant such as a liquefied gas such as liquefied petroleum gas (LPG) or a compressed gas can be used together with a concentrate containing polysulfated chondroitin sulfate and / or a salt thereof.

[0032] In addition to the above, the sweat gland function improving agent of the present invention may contain additives that are generally used as additives for pharmaceutical compositions or cosmetic compositions (for example, buffers, fragrances, colorants, ultraviolet absorbers, etc.).

[0033] The dosage and frequency of administration of the sweat gland function improving agent according to the present invention may be appropriately adjusted depending on the target disease and the severity of its symptoms, the concentration of polysulfated chondroitin sulfate and / or a salt thereof, age, body weight, etc. For example, polysulfated chondroitin sulfate is administered at a dose of 100 mg / kg per 1 cm of skin. 2 A dose of 0.03 μg to 30 mg, and preferably 0.3 μg to 3 mg, may be applied once or several times a day.

[0034] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. The symbols in the figures have the following meanings: ns "no significant difference", *P<0.05, **P<0.01, ***P<0.001

[0035] [Example 1] Histopathological observation 1-1: Changes in sweat glands due to aging The histopathological examination of the footpad skin of young and old mice was performed. As young mice, 6-8 week old C57BL / 6JJcl mice (B6 mice) were used (purchased from CLEA Japan, Inc.; hereafter referred to as young mice). As old mice, 76-79 week old B6 mice were used (purchased from Charles River Japan, Inc.; hereafter referred to as old mice). The skin of the mouse footpad was collected, fixed in 10% formaldehyde, and embedded in paraffin. After deparaffinization, the sections were stained with hematoxylin and eosin, and the condition of the sweat glands was confirmed under a microscope. The images taken are shown in Figure 1. As can be seen from Figure 1, it was confirmed that the lumen of the sweat glands was expanded in old mice compared to young mice.

[0036] 1-2: Changes in sweat glands due to continued steroid administration A preparation containing clobetasol propionate (Dermovate Cream [registered trademark] 0.05%, GlaxoSmithKline KK: hereafter referred to as CP) was applied to the footpads of young mice once a day (approximately 40 μL) for 4 weeks. To prevent the disappearance of CP, the entire foot, including the footpads, of the mice was covered with an elastic protective device after CP application (20 hours / day; hereafter referred to as occlusion administration). As a control, young mice were used that had undergone only the occlusion treatment (20 hours / day) for 4 weeks without CP application.

[0037] The condition of the sweat glands in the footpads of the CP-administered and control mice was then observed using the method described in 1-1. The photographed images are shown in Figure 2. As can be seen from Figure 2, the sweat glands of the mice that had only been occluded were in a similar state to the sweat glands of the young mice in Figure 1, but the sweat glands of the CP-administered mice were observed to have expanded lumen, similar to the sweat glands of the aged mice in Figure 1.

[0038] 1-3: Changes in sweat glands due to administration of heparinoids After 4 weeks of CP administration, a preparation containing a heparinoid (Hirudoid [registered trademark] Cream 0.3%, Maruho Co., Ltd.; hereafter referred to as MPS) was administered twice a day (approximately 40 μL / administration) to the footpads of young mice for 7 days by occlusion. Mice that had been administered CP for 4 weeks and then only occlusion treatment for 7 days were used as control mice.

[0039] After that, the condition of the sweat glands in the footpads of the MPS-administered mice and the control mice was observed using the method described in 1-1. The photographed images are shown in Figure 3. As can be seen from Figure 3, the sweat gland lumen, which expanded with repeated CP administration, did not shrink after the occlusion treatment. In contrast, in the MPS-administered mice, the sweat gland lumen contracted, and it was observed to be approaching the normal state before CP application.

[0040] [Example 2] Measurement of sweat gland lumen area 2-1: Changes in sweat gland lumen area with aging To quantify the expansion / contraction of the sweat gland lumen, the sweat gland lumen area was measured. The footpad skin of old mice and young mice that had been subjected to only the occlusion treatment for 4 weeks (n=5 each) was stained using the method described in 1-1. Then, the ratio of the lumen area to the area of ​​all sweat glands (excluding ducts) present in the evaluation area was calculated using Olympus cell Sens Dimensions (version 1.7) software (Olympus Corporation). The results (calculated mean value and standard error) are shown in Figure 4A. As is clear from Figure 4A, the ratio of the sweat gland lumen area was significantly increased in old mice compared to young mice.

[0041] 2-2: Changes in sweat gland lumen area due to continuous steroid administration and subsequent administration of heparinoids The sweat gland lumen area was measured by the method described above for young mice (n = 5) that underwent only occlusion treatment for 4 weeks, young mice (CP) that underwent CP occlusion administration for 4 weeks (n = 5), young mice that underwent occlusion treatment for 7 days after CP occlusion administration for 4 weeks (CP + occlusion treatment) (n = 8), young mice that underwent CP occlusion administration for 4 weeks and then MPS occlusion administration for 7 days (CP + MPS) (n = 8), and young mice that underwent CP occlusion administration for 4 weeks and then white petrolatum (Propeto [registered trademark], Maruishi Pharmaceutical Co., Ltd.; hereinafter, WP) occlusion administration for 7 days (CP + WP) (n = 8). CP was applied once a day at about 40 μL, MPS was applied twice a day at about 40 μL / application, and WP was applied twice a day at about 40 μg / application. The results are shown in Figure 4B. As is clear from Figure 4B, the ratio of the sweat gland lumen area increased with repeated administration of CP, and did not decrease even after subsequent occlusion treatment. In contrast, when MPS was administered, the ratio of the sweat gland lumen area that increased with CP administration was significantly decreased, and it was observed to recover to the same level as that of normal mice (mice only occluded) (no significant difference). The degree of decrease was insufficient with WP administration.

[0042] [Example 3]: Measurement of sweat rate 3-1: Decrease in sweating due to aging The number of sweat droplets from the footpads of young and old mice was measured using a method similar to the test method (impression mold technique: IMT) described in Clin Auto Res (2002) 12:20-23. In the IMT of this example, the impressions of sweat droplets generated from the sweat ducts and pressed against the mold were counted using a dissecting microscope to quantify the amount of sweat. The results are shown in Figure 5A (n=15 for young mice, n=12 for old mice). As is clear from FIG. 5A, sweating volume was reduced in aged mice compared with young mice.

[0043] 3-2: Recovery of sweating rate in aged mice by administration of heparinoids The number of sweat droplets from the footpads was measured by IMT in the same manner as in 3-1 for old mice that had been subjected to only occlusion treatment for 10 days, and old mice that had been administered MPS (twice a day, approximately 40 μL per administration) for 10 days. The results are shown in Figure 5B (n=6 / group). As is clear from FIG. 5B, the amount of sweating in the aged mice was not restored by occlusion alone, but it was confirmed that the amount of sweating was restored by application of MPS.

[0044] 3-3: Decreased sweating caused by repeated steroid administration The number of sweat droplets from the footpads was measured by IMT in the same manner as in 3-1 for mice before treatment (before CP application), mice after 4 weeks of CP occlusion (once a day, approximately 40 μL), and mice that underwent occlusion treatment for 7 days after the end of 4 weeks of CP occlusion. The results are shown in Figure 6A (n=15). As is clear from Figure 6A, repeated administration of CP reduced the amount of sweating compared to before CP application. Furthermore, even after cessation of CP administration and 7 days of occlusion, the reduced amount of sweating did not fully recover.

[0045] 3-4: Improvement of sweating rate by administration of heparinoids Mice that had been administered CP occlusion (once a day, about 40 μL) for 4 weeks were administered occlusion for 7 days, MPS occlusion for 7 days (twice a day, about 40 μL / time), or WP occlusion for 7 days (twice a day, about 40 μg / time), and then the number of sweat droplets was measured and the increase from the number of sweat droplets at the end of CP administration was calculated. The results are shown in Figure 6B (n=15). As shown in Figure 6B, the sweat rate decreased by repeated CP administration was not improved by occlusion alone (CP + occlusion), but was significantly improved by MPS administration (CP + MPS). In contrast, no significant improvement was observed with WP administration (CP + WP).

[0046] From the results of Examples 1 to 3, it was confirmed that in aged mice and mice repeatedly administered steroids, the lumen of the sweat gland is expanded and the amount of sweating is reduced. According to the present invention, it is possible to reduce the expanded lumen of the sweat gland by administering polysulfated chondroitin sulfate and / or a salt thereof, and as a result, it was confirmed that the reduced sweat gland function is restored.

Claims

1. A sweat gland function improver for improving sweat gland function that has decreased with age, comprising polysulfated chondroitin sulfate and / or a salt thereof as an active ingredient.

2. A sweat gland function improver as described in claim 1, used to restore decreased thermoregulatory function.

3. A sweat gland function improver described in claim 1 or 2, used to prevent heat stroke.

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