JP2007246459A - External preparation for skin, suitable for preventing, improving skin roughness - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a technique for improving the solubility of ursolic acid known to have an effect excellent in skin roughness, without deteriorating biological activity, thereby providing an external preparation for skin, useful for improving and preventing the skin roughness. <P>SOLUTION: This external preparation for skin, improving and preventing the skin roughness, containing an ursolic acid phosphate represented by a structure of chemical formula (1), and/or its salt as an active ingredient. The content of the ursolic acid phosphate and its salt is preferably 0.05 to 5 mass%, and it is preferable that the skin roughness is defined by the rise in transepidermal water loss (TEWL). Furthermore, it is preferable to contain a polyhydric alcohol in a total amount of 10 to 40 mass%. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to an external preparation for skin, and more particularly to an external preparation for skin suitable for preventing or improving rough skin.

  Triterpenic acids such as ursolic acid are known to have various physiological effects such as antioxidant action, anti-inflammatory action, and melanin production-suppressing action, and techniques for incorporating them into skin external preparations such as cosmetics are already known. (For example, refer to Patent Document 1, Patent Document 2, Patent Document 3, Patent Document 4, and Patent Document 5) Among these, ursolic acid is associated with an outless overload, whether transdermally or orally. There is a specific action to improve rough skin caused by failure of the skin microcirculation (see, for example, Patent Document 6, Patent Document 7, and Patent Document 8). However, these components are poorly soluble in oily components and aqueous components, so that there are problems such as precipitation in the preparation under long-term storage conditions, and improvement in solubility has been demanded. . In addition, in such a triterpenic acid, there is a concern that the excellent bioactivity of these substance groups is not fully exhibited due to poor solubility due to poor solubility. Under such circumstances, there has been a movement for those skilled in the art to improve the solubility of triterpenic acid. As a study for improving the solubility, for example, derivatization of an ester or the like has been performed and the solubility in an oily component has been improved. However, the phenomenon such as precipitation has not been fully solved yet. (See, for example, Patent Document 9). That is, there has been a demand for means for improving the solubility of triterpenic acids such as ursolic acid, which have various physiological activities, without impairing the physiological activities.

  On the other hand, a technique for phosphorylating a hydroxyl group of a compound having a hydroxyl group to derive a phosphate ester is already known, and in the cosmetics field, phosphorous is used for the purpose of stabilizing a sugar such as ascorbic acid or a sugar analogue. Chemical modification to acid ester derivatives has been performed (see, for example, Patent Document 7 and Patent Document 10), but there is no example of phosphorylation for the purpose of improving solubility, and phosphorous of triterpenic acid. An oxide is a novel compound not described in any literature. Therefore, it is not known at all to contain this as an active ingredient in cosmetics for improving or preventing rough skin.

Japanese Patent Laid-Open No. 08-165231 Japanese Patent Laid-Open No. 08-208424 Table 01/072265 Japanese Patent Laid-Open No. 11-012122 JP 2000-302659 A JP 2004-67676 A JP 2003-321369 A JP 2003-160429 A JP 2004-331593 A JP 2001-354513 A

  The present invention has been made under such circumstances, and in ursolic acid, which is known to have an excellent effect on rough skin, provides a technique for improving solubility without impairing physiological activity, This makes it a subject to provide the skin external preparation useful for improvement and prevention of rough skin.

In view of such a situation, the present inventors have sought for a technique for improving the solubility of ursolic acid, which is known to have an excellent effect on rough skin, without impairing physiological activity. As a result of repeated efforts, it has been found that phosphorylated ursolic acid (ursolic acid phosphate ester), which is obtained by phosphorylating the hydroxyl group of ursolic acid, has such characteristics, and is incorporated into an external preparation for skin. As a result, it has been confirmed that the present invention is effective in preventing and improving rough skin, and the present invention has been completed. That is, the present invention is as follows.
(1) A skin external preparation for improving or preventing rough skin, comprising ursolic acid phosphate ester and / or a salt thereof as an active ingredient and having the following structure.

ウルソール酸リン酸エステル

Ursolic acid phosphate

(2) Content of said ursolic acid phosphate ester and its salt is 0.05-5 mass%, The skin external preparation for the improvement or prevention of rough skin as described in (1) characterized by the above-mentioned.
(3) The skin external preparation according to (1) or (2), wherein the rough skin is defined by an increase in transdermal water dispersion loss (TEWL).
(4) The skin external preparation according to any one of (1) to (3), further comprising 10 to 40% by mass of polyhydric alcohol in a total amount.
(5) The external preparation for skin according to (4), wherein glycerin is contained as the polyhydric alcohol.
(6) Content of glycerol is 1-5 mass%, The skin external preparation as described in (5) characterized by the above-mentioned.
(7) As polyhydric alcohols other than glycerin, 1 to 2 or more selected from the following are contained in a total amount of 10 to 20% by mass based on the total amount of the external preparation for skin, The external preparation for skin according to (5) or (6).
(Polyhydric alcohols other than glycerin)
Dipropylene glycol, 1,2-pentanediol, 1,2-hexanediol, 1,2-octanediol, isoprene glycol (8) The skin external preparation according to (7), characterized by not containing parabens.

  According to the present invention, in ursolic acid, which is known to have an excellent effect on rough skin, a technique for improving solubility without impairing physiological activity is provided, thereby being useful for improving and preventing rough skin. Can be provided.

(1) Ursolic acid phosphate ester which is an essential component of the skin external preparation of the present invention The skin external preparation of the present invention is used exclusively for the improvement or prevention of rough skin, and phosphorous ursolic acid as an essential component It contains an acid ester and / or a physiologically acceptable salt thereof as an active ingredient. Here, “as an active ingredient” means that the improvement or prevention of rough skin is recognized as an effect and efficacy of quasi-drugs in the Pharmaceutical Affairs Law. It is preferable to show use as an active ingredient for “improvement and prevention of rough skin” in “quasi-drug”. This is different from normal cosmetics, etc. by using it in such a form of use, and in compliance with the form of use and precautions for use, without causing any loss of the effect of the active ingredient. It is because it can do.

  In the present invention, rough skin is a general term for abnormalities in skin surface morphology, which is caused by an increase in transcutaneous water dispersion loss (TEWL) caused by a decrease in skin barrier function. There is a case involving such as. The cause is said to be difficult to maintain the skin surface form due to the failure of the skin microcirculation. In some cases, inflammatory factors such as interleukins are released as a result of such skin tissue shedding, resulting in secondary inflammation, but this inflammation is caused by abnormal skin surface morphology. Unless it is improved, it is said that it is difficult to heal, and this improvement is said to be important in improving the rough skin itself, even in the sense of healing the inflammation that sometimes appears with rough skin. Yes. In such general conditions of rough skin, ursolic acid phosphate ester and / or salt thereof, which is an essential component of the external preparation for skin of the present invention, suppresses the above-mentioned TEWL enhancement and causes abnormal skin surface morphology. Has a preventive action. That is, in other words, in the present invention, rough skin can be defined as an increase in TEWL, with an increase of 15% or more, more strictly 25% or more, relative to the normal TEWL value, In the present invention, it is defined as being in a rough skin state.

  Thus, the ursolic acid phosphate ester contained as an essential component in the external preparation for skin of the present invention can be produced by the following method. That is, it is a method of inducing ursolic acid to a phosphate ester, which may be carried out in accordance with a generally known phosphorylation method. For example, ursolic acid is converted into 1 to 3 equivalents of diethyl-N, N. It can be produced by treating with diethylphosphoroamidate in the presence of tetrazole, reacting with t-butyl hydroperoxide to form a methyl phosphate form of ursolic acid, and further allowing bromotrimethylsilane to act. The ursolic acid phosphate obtained by treating ursolic acid in this way has the structure shown above. The phosphorylated ursolic acid (ursolic acid phosphate ester) thus obtained can be converted into a salt by reacting with an alkali usually used in pharmaceuticals and cosmetics. Examples of such salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium and magnesium, organic amine salts such as ammonium salts, triethanolamine salts, and triethylamine salts, lysine salts, Preferred examples include basic amino acid salts such as arginine salts. Among these, the use as a potassium salt is particularly preferable from the viewpoint of ease of handling. The ursolic acid phosphate ester or salt thereof thus obtained exhibits remarkable solubility in an aqueous carrier, and its drug utilization is significantly improved compared to the original ursolic acid. When the ursolic acid phosphate ester and / or salt thereof of the present invention is contained in a skin external preparation for improving or preventing rough skin, the content is converted into the ursolic acid phosphate ester and applied to the skin. 0.05-5 mass% is suitable with respect to the agent whole quantity, and 0.1-1 mass% is especially preferable. This is because if the amount is too small, the improvement or prevention activity of rough skin may not occur, and if the amount is too high, the improvement or prevention activity of rough skin may reach its peak. The production examples of ursolic acid phosphate are shown below.

(Production example)
A mixture of ursolic acid (48.1 g, 0.105 mol), dimethyl-N, N-diethyl phosphoramidate (Dimethyl N, N-diethylphosphoramidate; 34.82 g, 0.211 mol) and dry tetrahydrofuran (1250 ml) was added at 35 ° C. After heating to a clear solution, 1-H tetrazole (44.25 g, 0.632 mol) was added at once at an internal temperature of 27 ° C., and the mixture was stirred at room temperature (22 ° C.) for 1 hour. After confirming the formation of dimethyl phosphite by TLC, the reaction solution was cooled with acetone / dry ice, and 70% t-butyl hydroperoxide aqueous solution (84 mL, 0.607 mol) was added dropwise at −20 ° C. The temperature was gradually returned to room temperature except for the cooling bath, and disappearance of dimethyl phosphite and formation of dimethyl phosphate were confirmed by TLC, and then the reaction was stopped at 0 ° C. with a 10% aqueous sodium bisulfite solution (300 ml). Ethyl acetate (1250 mL) was added to the reaction solution, and the organic layer was separated. The organic layer was washed successively with 10% aqueous sodium hydrogen sulfite solution (100 ml × 3), 5% aqueous sodium hydrogen carbonate solution (200 ml × 3) and saturated brine, and then dried over anhydrous magnesium sulfate. Silica gel (400 mL) was added to the organic layer and concentrated to dryness under reduced pressure. Silica gel (400 mL) was charged to the sum, and the adsorbed silica gel was charged with hexane, and then developed with hexane / ethyl acetate (2: 1). The fraction with a single composition was concentrated to obtain 35 g of the title compound as a gel powder. As for this thing, absorption of the dichloromethane used for washing with ethyl acetate by NMR was recognized. In addition, 6 g was obtained as a fraction containing slightly impurities. Ursolic acid 3-methyl phosphate (35 g 62 mmol) synthesized in this way was dissolved in dry dichloromethane (350 ml), and bromotrimethylsilane (25 mL, 186 mmol) was added under an argon stream at room temperature. The reaction was carried out for 1 hour. After confirming TLC, the solution was concentrated under reduced pressure, and the residue was dissolved and concentrated in again dried toluene (200 ml × 2) to completely remove excess bromotrimethylsilane. The concentrate 95% methanol (300 mL) was added and dissolved, and the mixture was stirred at room temperature for 1 hour to precipitate crystals. After concentrating under reduced pressure as it was, it was dried overnight under reduced pressure over anhydrous phosphoric acid at 50 ° C. to obtain 23.5 g of ursolic acid phosphate.
¹ H-NMR (ppm): 5.23 (m, 1H), 3.87 (m, 1H), 2.20 (d, 1H), 2.05-1.25 (m, 25H), 12 (s, 3H), 1.02 (s, 3H), 0.99 (s, 3H), 0.97 (d, 3H), 0.87 (d, 3H), 0.85 (s, 3H) )
Mass: 535 (M ⁺ )
IR (cm ⁻¹ ): 2948, 1694, 1456, 1378, 1028, 661, 566

(2) External preparation for skin of the present invention The external preparation for skin of the present invention contains the essential components as active ingredients, and is for improving or preventing rough skin. Since the external preparation for skin of the present invention is exclusively used for improving or preventing rough skin noise, it is more preferable to contain a component having a preferable action against rough skin. As such a component-like structure, it can be illustrated that the polyhydric alcohol is contained in a total amount of 10 to 40% by mass, more preferably 15 to 30% by mass. Such polyhydric alcohol preferably contains glycerin, and the preferred content of glycerin is preferably 1 to 5% by mass. In addition to glycerin, 10-20% by mass of one or more selected from dipropylene glycol, 1,2-pentanediol, 1,2-hexanediol, 1,2-octanediol and isoprene glycol It is preferable that such a content secures antiseptic power and does not contain parabens such as methyl paraben, ethyl paraben, propyl paraben, and butyl paraben. This is because, in the skin condition where the skin barrier function is reduced such as rough skin, administration of parabens that may cause transient irritation (stigging) This is because the possibility of triggering is increased and the effect of improving rough skin may be impaired. One or more polyhydric alcohols selected from the above-mentioned dipropylene glycol, 1,2-pentanediol, 1,2-hexanediol, 1,2-octanediol and isopreneglycol have antiseptic properties. In addition, it is possible to prevent a decrease in preservative power due to the absence of parabens.

  In the external preparation for skin of the present invention, in addition to the above-mentioned components, various components generally used for pharmaceuticals, cosmetics and the like, that is, aqueous components, oily components, powder components, surfactants, moisturizers, thickeners, colors 1 or 2 or more kinds of agents such as agents, fragrances, antioxidants, pH adjusters, chelating agents, preservatives, UV protection agents, anti-inflammatory agents, wound healing agents, metabolism promoters, whitening agents, etc. be able to.

  Examples of the aqueous component include water, lower alcohols (ethanol, propanol, isopropanol) and the like.

  Examples of the oil component include higher fatty acids (such as stearic acid, palmitic acid, myristic acid, lauric acid, and esters thereof), higher alcohols (such as cetanol, lanolin alcohol, stearyl alcohol, cetostearyl alcohol) and waxes ( Solid paraffin, microcrystalline wax, ceresin wax, polyethylene wax, beeswax, wood wax, carnauba wax, candelilla wax, etc., natural or synthetic oils (squalane, liquid paraffin, lanolin or derivatives thereof, olive oil, camellia oil, cottonseed oil, oleyl Alcohol, castor oil, petrolatum, adipic acid diethoxyethyl ester, silicon oil, fluorinated hydrocarbon, etc.).

  Examples of the powder component include aluminum oxide, titanium dioxide, zinc oxide, red iron oxide, yellow iron oxide, ultramarine blue, bitumen, acrylic resin powder, silica, talc, sericite, mica, titanium mica, and the like.

  Examples of the surfactant include anionic surfactants such as fatty acid soap (sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, alkylethanol triethanolamine ether; stearyltrimethylammonium chloride, benzalkonium chloride, lauryl Cationic surfactants such as amine oxides; imidazoline-based amphoteric surfactants (2-cocoyl-2-imidazolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), betaine-based surfactants (alkylbetaines, amides) Amphoteric surfactants such as betaine, sulfobetaine, etc .; sorbitan fatty acid esters (such as sorbitan monostearate, sorbitan sesquioleate), glycerin fatty acids (glyceryl monostearate) Propylene glycol fatty acid esters (such as propylene glycol monostearate), hardened castor oil derivatives, glycerin alkyl ether, POE sorbitan fatty acid esters (POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbit Fatty acid esters (POE-sorbitol monolaurate, etc.), POE glycerin fatty acid esters (POE-glycerin monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE2) -Octyldodecyl ether, etc.), POE alkyl phenyl ethers (POE nonyl phenyl ether, etc.), Pluronic types, POE / POP alkyl ether Nonionic surface actives such as POE / POP2-decyltetradecyl ether, Tetronics, POE castor oil / hardened castor oil derivatives (POE castor oil, POE hardened castor oil, etc.), sucrose fatty acid esters, alkyl glucosides, etc. Examples include agents.

  As the humectant, for example, diglycerin, triglycerin, sorbit or a derivative thereof, polyhydric alcohol such as polyethylene glycol; glucose, maltose, maltitol, sucrose, fructose, threitol, erythritol, sorbitol, amylolytic sugar, hyaluronic acid, Examples thereof include chondroitin sulfate, hydrolyzed collagen, hydrolyzed elastin, carboxymethyl chitin, casein soda, mucin, glycosphingolipid, and the like, and is blended in the range of 0.1 to 30% by weight with respect to the whole.

  Examples of the thickener include carboxyvinyl polymer, CP jelly, carboxymethylcellulose, carrageenan, sodium alginate, bentonite, bee gum, synthetic hectorite and the like.

  Examples of the antioxidant include dibutylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherol-sodium pyrosulfite, sodium bisulfate, tocopherol acetate and the like.

  Examples of the pH adjuster include citric acid, lactic acid, tartaric acid, and phosphoric acid.

  Examples of the chelating agent include EDTA (ethylenediaminetetraacetic acid).

  Examples of the preservative include methyl, ethyl, propyl, butyl ester of p-oxybenzoic acid, phenoxyethanol, o-phenylphenol, dehydroacetic acid or a salt thereof, p-cresol, m-cresol, o-chloro-m-xylenol, etc. Is mentioned.

  Examples of the UV protection agent include urocanic acid or a derivative thereof, isoferulic acid or a salt thereof, oxybenzone or a derivative thereof, p-aminobenzoic acid or a derivative thereof, dibenzoylmethane or a derivative thereof, p-methoxycinnamic acid or a derivative thereof, and the like. It is mentioned and it mix | blends in 0.01-30 weight% with respect to the whole.

  Examples of the anti-inflammatory agent include glycyrrhetinic acid or a derivative thereof such as stearyl glycyrrhetinic acid, glycyrrhizic acid or a salt thereof, a Maronnier extract, an aloe extract, and the like, in a range of 0.01 to 5% by weight with respect to the whole. Blended.

  Examples of the wound healing agent include royal jelly extract, toki extract, rosemary extract, rosmarinic acid and the like, and are blended in the range of 0.01 to 5% by weight based on the whole.

  Examples of the metabolism promoter include placenta extract, γ-oryzanol, amino acids or derivatives thereof, vitamin E or derivatives thereof, and the like, and is blended in the range of 0.01 to 5% by weight.

  Examples of whitening agents include pantethein-S-sulfonic acid, ascorbic acid or magnesium phosphate thereof, arbutin, kojic acid, linoleic acid, tranexamic acid, esculin and the like.

  The skin external preparation of this invention can be manufactured by processing the said essential component and arbitrary components in accordance with a conventional method. The skin external preparation of the present invention thus obtained suppresses the enhancement of TEWL, and thus has an excellent improvement effect on rough skin and a rough skin prevention effect. As the rough skin prevention effect, rough skin is further deteriorated. The effect which prevents doing and the effect which prevents the skin which has not yet roughened skin from roughening are mentioned. For this reason, it is preferable to administer the skin external preparation of this invention to the location where rough skin exists, or the location where rough skin may arise. The skin external preparation of the present invention is not particularly limited as long as it is externally administered to the skin, and specific examples thereof include cosmetics, skin external medicines, skin external goods, etc. In order to make the best use of the effect, it is preferably applied to cosmetics for rough skin. In particular, as an active ingredient for “improvement and prevention of rough skin” in “quasi-drugs”, the topical skin application of the present invention It is preferable to apply to quasi-drugs indicating the use of ursolic acid phosphate ester and / or its salt, which is an essential component of the agent.

  Hereinafter, the present invention will be described in more detail with reference to examples, but it is needless to say that the present invention is not limited to such examples.

  A lotion cosmetic, which is an external preparation for skin of the present invention, was produced according to the formulation shown below. That is, the formulation components were stirred and solubilized at 80 ° C., and then cooled with stirring to obtain a lotion cosmetic 1. Moreover, the same operation was performed, and the comparative example 1 which substituted the ursolic acid phosphate potassium salt with water was also created.

<Rough skin improvement test>
Using a rough skin model induced by a 5% by weight sodium lauryl sulfate (SDS) aqueous solution using 21 male employees (age 25 to 50 years old), this lotion cosmetic 1 and Comparative Example 1 were used as samples. The improvement effect on was tested. That is, two 1.5 cmφ portions were provided on the inner side of the forearm, and after measuring transcutaneously dissipated moisture (TEWL) with “Tevameter” manufactured by Integral, 5 mass% SDS aqueous solution was added on the first day, Administered on days 3, 3 and 4. (4 times administration) The sample was administered to the same site as the SDS aqueous solution 30 minutes after the administration of the 5 mass% SDS aqueous solution from the 1st day to the 4th day, on the 5th day, 6th day and 7th day. (Seven times administration) TEWL was measured before SDS administration on the fourth day and before sample administration on the fifth day. The values obtained by subtracting the TEWL value on the test start date from the TEWL values on the 4th and 5th days were designated as “ΔTEWL”, and this value was used as an evaluation target. This value was analyzed by Wilcoxon rank sum test. This work procedure is shown in Table 2. The results are shown in Table 3. From this result, it can be seen that the external preparation for skin of the present invention is excellent in rough skin improvement effect.

  The present invention can be applied to an external preparation for skin, such as a quasi-drug for improving or preventing rough skin.

Claims (8)

A skin external preparation for improving or preventing rough skin, comprising ursolic acid phosphate ester and / or a salt thereof as an active ingredient, the structure of which is shown below.

Ursolic acid phosphate The external preparation for skin according to claim 1, wherein the content of the ursolic acid phosphate and its salt is 0.05 to 5% by mass. The skin external preparation according to claim 1 or 2, wherein the rough skin is defined by an increase in transdermal water dispersion loss (TEWL). The skin external preparation according to any one of claims 1 to 3, further comprising a polyhydric alcohol in a total amount of 10 to 40% by mass. The external preparation for skin according to claim 4, wherein glycerin is contained as the polyhydric alcohol. The skin external preparation according to claim 5, wherein the content of glycerin is 1 to 5% by mass. The polyhydric alcohol other than glycerin contains 1 to 2 or more kinds selected from the following, in a total amount of 10 to 20% by mass based on the total amount of the external preparation for skin, characterized in that: Or the skin external preparation of 6.
(Polyhydric alcohols other than glycerin)
Dipropylene glycol, 1,2-pentanediol, 1,2-hexanediol, 1,2-octanediol, isoprene glycol The external preparation for skin according to claim 7, which does not contain paraben.