JP2007238463A - Ror activation agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an agent for activating retinoid-related orphan receptor (ROR). <P>SOLUTION: The invention relates to an ROR activation agent containing a compound expressed by chemical formula (1) and/or its salt. In the formula, R<SB>1</SB>and R<SB>2</SB>are each selected from hydrogen, alkyl group, aryl group, acyl group and ethylene acetate. The compound expressed by chemical formula (1) and/or its salt have excellent ROR activation effect and are useful for the amelioration of skin aging symptoms such as dry skin, fine wrinkle, dull skin, distorted texture, etc., and skin diseases caused by the differentiation disorder of epidermal cell. There is no particular restriction on the form of the ROR activation agent and the agent can be used in ordinary medicines, quasi-drugs, cosmetics or foods in the form of tablet, granule, drink, emulsion, etc. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

The present invention relates to a retinoid-related orphan receptor (ROR) activator comprising a compound represented by the chemical formula (1) and / or a salt thereof as an active ingredient, which is an invention in the technical field relating to prevention and improvement of skin aging. About.

  The skin is prone to generate active oxygen under the influence of ultraviolet rays, and is constantly exposed to the oxygen stress, which is considered to be the root cause of skin aging. Wrinkles, which are one type of skin aging, are caused by a decrease in skin elasticity due to a decrease and degeneration of extracellular matrix components such as collagen. In the dermis of skin exposed to such ultraviolet rays, expression of matrix metalloprotease (MMP) having a resolution with respect to extracellular matrix components is enhanced. On the other hand, interleukin (IL) -1, IL-6, COX-2, VCAM-1, and ICAM-1 are involved in skin diseases and skin aging associated with abnormal skin immunity and abnormal differentiation of epidermal cells (non-patent literature). 1, 2).

Wlaschek M et al., Photochem. Photobiol. , 1994, 59, 550-556. Norris P et al. Invest. Dermatol. 1991, 96, 763-770.

  Expression of such MMPs, inflammatory cytokines, and adhesion molecules is regulated by NF-κB, which is one of transcription factors (Non-patent Documents 3-5). That is, NF-κB usually forms an inactive complex with the inhibitory protein IκB and exists in the cytoplasm. However, when IκB is degraded by stimulation with cytokines such as TNF-α and the ability to control NF-κB is lost, the activated NF-κB moves into the nucleus and binds to the promoter region of the DNA to bind to the gene. The transfer is started (Non-Patent Documents 6 and 7).

Han YP et al. Cell Science, 2000, 114, 131-139 Yuan W et al. Biol. Chem. , 2001, 276, 38502-38510 Fiber C et al. Cell Science, 2004, 117, 359-367 Forman B et al., Science, 1998, 242, 540-546. Bauerle P.M. A et al., Cell, 2004, 87, 13-20

  The retinoid-related orphan receptor (ROR) is one of the transcription factors included in the nuclear receptor superfamily. Although ROR is known only for the presence of genes and proteins, it has been identified as an orphan receptor because no actual physiological function or in vivo ligand has been identified, and ROR is an RORα, RORβ, RORγ Three types are known (Non-Patent Document 8). RORα has a common DNA-binding domain and a ligand-binding domain, and there are four types of isoforms with different N-termini, and binds to DNA with a monomer to regulate transcription of the gene (Non-patent Document 9).

Jetten A.J. M et al., Prog. Nucleic Acid Res. Mol. Biol. 2001, 69, 205-247. Giguere V et al., Mol. Cell. Biol. 1995, 15, 2517-2526.

  Furthermore, it has been clarified that the target gene of ROR acting as a suppressor of atherosclerosis and rheumatoid arthritis is IκB, and ROR is an extremely important transcription located upstream in suppressing NF-κB. It is suggested that this is a factor (Non-patent Document 10).

Deliverive P et al., EMBO reports, 2001, 21, 42-48.

  ROR is considered to be a protein useful for controlling the expression of MMP and inflammatory cytokines via the NF-κB pathway, and is expected to be applied to an anti-aging composition. However, it is impossible to formulate ROR directly from the viewpoint of stability, safety, and effect, and it is uneconomical. For this reason, a method for activating ROR in the skin is good, and in particular, development of an ROR activator is desired.

  Under such circumstances, the present inventors have intensively studied and found that the compound represented by the chemical formula (1) and / or a salt thereof is stable and exhibits an excellent ROR activation effect. It came to complete.

  The chemical formula (1) of the present invention can be naturally derived and can be synthesized from tocopherol by a conventional method, and the following documents can also be referred to.

JP-B 61-20583 JP 3-32558

  In the present invention, the salt represented by the chemical formula (1) can also be used, and the kind of the salt is not limited. Generally, alkali metal salts such as sodium and potassium, and alkaline earth metal salts such as calcium and magnesium are used. Used.

  The ROR activator of the present invention can be used for any of pharmaceuticals, quasi drugs, cosmetics or foods. Examples of the dosage form include powders, pills, tablets, injections, suppositories, and emulsions. , Capsules, granules, liquids (including tinctures, fluid extracts, spirits, suspensions, limonades, etc.), lotions, creams, emulsions, gels, aerosols, packs, cleaning agents, bath preparations , Foundation, powder, lipstick, ointment, poultice, paste, plaster, essence, tablet confectionery, beverage and the like. In addition, various components used for normal cosmetics, quasi drugs, pharmaceuticals, etc., for example, oily ingredients, emulsifiers, moisturizers, thickeners, medicinal ingredients, preservatives, pigments, as long as the effects of the present invention are not impaired. , Powders, pH adjusters, ultraviolet absorbers, antioxidants, fragrances, and the like can be appropriately blended.

  Examples of the oil component include liquid paraffin, petrolatum, microcrystalline wax, squalane, jojoba oil, beeswax, carnauba wax, lanolin, olive oil, coconut oil, higher alcohol, fatty acid, ester of higher alcohol and fatty acid, and silicone oil. Examples of the emulsifier include nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, and polyoxyethylene hydrogenated castor oil. And anionic surfactants such as sodium stearoyl lactate, amphoteric surfactants such as soybean phospholipid, and cationic surfactants such as alkyltrimethylammonium chloride. Examples of the humectant include glycerin, sorbitol, xylitol, maltitol, propylene glycol, polyethylene glycol, 1,3-butylene glycol and the like. Examples of the thickening agent include clay minerals such as carboxyvinyl polymer, xanthan gum, methyl cellulose, polyvinyl pyrrolidone, gelatin, and bentonite. Examples of medicinal ingredients include various vitamins and derivatives thereof, allantoin, glycyrrhizic acid and derivatives thereof, and various animal and plant extracts.

  The amount of the compound to be blended in the ROR activator of the present invention varies depending on the dosage form and the expected effect, but is usually 0.001% by weight or more, preferably about 0.1 to 50% by weight. Is good. If it is less than 0.001% by weight, a sufficient effect may be difficult to expect, and if it exceeds 50% by weight, an increase in the effect is hardly recognized and it is uneconomical.

  The novel medicinal component of the present invention has an ROR activation effect, controls the NF-κB pathway through increased expression of IκB, and prevents aging of living tissues.

  Next, the effects of the present invention will be described with specific examples. These examples specifically illustrate the effect and do not limit the scope of the invention. The compounding quantity in an Example is weight%.

  The medicinal component of the present invention can be formulated as a formulation example as follows.

Formulation Example-1 Beverage Formulation Blending amount (%)
1. dl-α-Tocopheryl sodium phosphate 2.0
2. Citric acid 0.7
3. Fructose dextrose liquid sugar 60.0
4). Perfume appropriate amount 5. Bring the total amount to 100 with purified water.
[Production method] Add 1 to 4 to 5, dissolve by stirring, filter, heat sterilize, and fill into a 50 mL glass bottle.

Formulation Example-2 Beverage Formulation Blending amount (%)
1. d-α-Tocopheryl sodium phosphate 1.0
2. Citric acid 0.7
3. Sucrose 60.0
4). Perfume appropriate amount 5. Bring the total amount to 100 with purified water.
[Production method] Add 1 to 4 to 5, dissolve by stirring, filter, heat sterilize, and fill into a 50 mL glass bottle.

Formulation Example-3 Granule Formulation Blending amount (%)
1. dl-α-Tocopheryl phosphate disodium 3.0
2. Reduced maltose syrup 38.0
3. Microcrystalline cellulose 59.0
[Manufacturing method] An appropriate amount of 70% ethanol is added to components 1 to 3, kneaded, extruded and granulated, and dried to obtain granules.

Formulation Example-4 Tablet Formulation Blending amount (%)
1. d-α-Tocopheryl potassium phosphate 4.0
2. Dried corn starch 25.0
3. Reduced maltose syrup 20.0
4). Powdered sugar 48.0
5). Sucrose fatty acid ester 3.0
[Manufacturing method] An appropriate amount of 70% ethanol is added to components 1 to 4, kneaded, extruded and granulated, and dried to obtain granules. Ingredient 5 is added to the granules and tableted to give 0.52 g tablets.

Formulation example-5 Tablet confection Formulation amount (%)
1. dl-α-Tocopheryl sodium phosphate 0.9
2. Dried corn starch 51.1
3. Erythritol 39.0
4). Citric acid 5.0
5). Sucrose fatty acid ester 3.0
6). Fragrance 1.0
[Manufacturing method] An appropriate amount of water is added to components 1 to 4, kneading, extrusion granulation, and drying to obtain granules. Ingredients 5 and 6 are added to the granules and tableted to obtain 1.0 g of tablet confectionery.

Formulation Example-6 Capsule Formulation Formulation Amount (%)
1. dl-α-tocopheryl sodium phosphate 15.0
2. Cellulose 85.0
[Manufacturing method] Components 1 and 2 are mixed, and a No. 2 hard capsule is filled with 250 mg to obtain a capsule.

Formulation Example-7 Cream Amount (%)
Formula 1. dl-α-Tocopheryl sodium phosphate 2.0
2. Squalane 5.5
3. Olive oil 3.0
4). Stearic acid 2.0
5). Beeswax 2.0
6). Octyldodecyl myristate 3.5
7). Polyoxyethylene cetyl ether (20E.O.) 3.0
8). Behenyl alcohol 1.5
9. Glycerol monostearate2.5
10. Fragrance 0.1
11.1,3-butylene glycol 8.5
12 Ethyl paraoxybenzoate 0.05
13. Methyl paraoxybenzoate 0.2
14 Make the total volume 100 with purified water
[Manufacturing method] Components 2 to 9 are heated and dissolved and mixed, and kept at 70 ° C to obtain an oil phase. Ingredients 1 and 11 to 14 are dissolved by heating and mixed, and kept at 75 ° C. to obtain an aqueous phase. The aqueous phase is added to the oil phase to emulsify, and the mixture is cooled while stirring. The component 10 is added at 45 ° C., and further cooled to 30 ° C. to obtain a product.

Comparative Example-1 Conventional Cream In Formulation Example-7, a product obtained by replacing dl-α-tocopheryl phosphate with purified water was used as a conventional cream.

Formulation example-8 lotion amount (%)
Formula 1. d-α-Tocopheryl sodium phosphate 0.1
2. 1,3-butylene glycol 8.0
3. Glycerin 2.0
4). Xanthan gum 0.02
5). Citric acid 0.01
6). Sodium citrate 0.1
7). Ethanol 5.0
8). Methyl paraoxybenzoate 0.1
9. Polyoxyethylene hydrogenated castor oil (40E.O.) 0.1
10. Perfume proper amount11. Make the total volume 100 with purified water
[Production method] Components 1 to 6 and 11 and components 7 to 10 are uniformly dissolved, mixed and filtered to obtain a product.

Formulation Example-9 Emulsion Formulation Amount (%)
Formula 1. dl-α-Tocopheryl phosphate disodium 0.5
2. Squalane 5.0
3. Olive oil 5.0
4). Jojoba oil 5.0
5). Cetanol 1.5
6). Glycerol monostearate 2.0
7). Polyoxyethylene cetyl ether (20E.O.) 3.0
8). Polyoxyethylene sorbitan monooleate (20E.O.) 2.0
9. Fragrance 0.1
10. Propylene glycol 1.0
11. Glycerin 2.0
12 Methyl paraoxybenzoate 0.2
13. Make the total volume 100 with purified water
[Manufacturing method] Components 2 to 8 are dissolved by heating and mixed, and kept at 70 ° C to obtain an oil phase. Ingredients 1 and 10-13 are dissolved by heating and mixed, and kept at 75 ° C. to form an aqueous phase. The aqueous phase is added to the oil phase to emulsify, and the mixture is cooled while stirring. The component 9 is added at 45 ° C., and further cooled to 30 ° C. to obtain a product.

Formulation Example -10 Gel formulation (%)
Formula 1. d-α-Tocopheryl potassium phosphate 0.1
2. Ethanol 5.0
3. Methyl paraoxybenzoate 0.1
4). Polyoxyethylene hydrogenated castor oil 0.1
5). Perfume appropriate amount 6.1,3-butylene glycol 5.0
7). Glycerin 5.0
8). Xanthan gum 0.1
9. Carboxyvinyl polymer 0.2
10. Potassium hydroxide 0.2
11. Make the total volume 100 with purified water
[Manufacturing method] Components 2 to 5 and components 1 and 6 to 11 are uniformly dissolved and mixed to obtain a product.

Formulation Example-11 Ointment Amount (%)
Formula 1. dl-α-tocopheryl sodium phosphate 1.0
2. Polyoxyethylene cetyl ether (30E.O.) 2.0
3. Glycerol monostearate 10.0
4). Liquid paraffin 5.0
5). Cetanol 6.0
6). Methyl paraoxybenzoate 0.1
7). Propylene glycol 10.0
8). Make the total volume 100 with purified water
[Manufacturing method] Components 2 to 5 are dissolved by heating and mixed, and kept at 70 ° C to obtain an oil phase. Ingredients 1 and 6 to 8 are dissolved by heating and mixed, and kept at 75 ° C. to form an aqueous phase. The aqueous phase is added to the oil phase to emulsify, and the product is cooled to 30 ° C. with stirring to obtain a product.

Formulation example -12 pack compounding amount (%)
Formula 1. dl-α-Tocopheryl potassium phosphate 0.1
2. Polyvinyl alcohol 12.0
3. Ethanol 5.0
4.1,3-Butylene glycol 8.0
5). Methyl paraoxybenzoate 0.2
6). Paraoxyethylene hydrogenated castor oil (20 EO) 0.5
7). Citric acid 0.1
8). Sodium citrate 0.3
9. Perfume appropriate amount10. Make the total volume 100 with purified water
[Production Method] Components 1 to 10 are uniformly dissolved to obtain a product.

Formulation Example-13 Foundation Formulation (%)
Formula 1. d-α-Tocopheryl phosphate disodium 1.0
2. Stearic acid 2.4
3. Polyoxyethylene sorbitan monostearate (20E.O.) 1.0
4). Polyoxyethylene cetyl ether (20E.O.) 2.0
5). Cetanol 1.0
6). Liquid lanolin 2.0
7). Liquid paraffin 3.0
8). Isopropyl myristate 6.5
9. Butyl paraoxybenzoate 0.1
10. Sodium carboxymethylcellulose 0.1
11. Bentonite 0.5
12 Propylene glycol 4.0
13. Triethanolamine 1.1
14 Methyl paraoxybenzoate 0.2
15. Titanium dioxide 8.0
16. Talc 4.0
17. Bengala 1.0
18. Yellow iron oxide 2.0
19. Perfume proper amount20. Make the total volume 100 with purified water
[Manufacturing method] Components 2 to 9 are heated and dissolved and kept at 80 ° C to obtain an oil phase. Swell component 10 well with component 20, then add components 1 and 11-14 and mix uniformly. To this, components 15 to 18 pulverized and mixed with a pulverizer are added, cooled, component 19 is added at 45 ° C., and cooled to 30 ° C. with stirring to obtain a product.

Formulation Example-14 Bath Agent Formulation (%)
Formula 1. dl-α-tocopheryl sodium phosphate 1.0
2. Sodium bicarbonate 50.0
3. Yellow 202 No. 4 Perfume appropriate amount 5. Make the total amount 100 with anhydrous sodium sulfate
[Production method] Components 1 to 5 are uniformly mixed to obtain a product.

  Next, experimental examples will be given to explain the effects of the present invention in detail.

Experimental Example 1 Expression Analysis of RORα mRNA A sample was added to normal human keratinocytes in a confluent state so as to be 50 μM, and total RNA was extracted 24 hours later. RORα mRNA expression level was measured by RT-PCR method based on total RNA. The RT-PCR method is described in TaKaRa RNA PCR Kit (AMV) Ver. 2.1 was used. GAPDH was used as an internal standard. Other operations were carried out according to a predetermined method, and the PCR reaction solution was subjected to agarose gel electrophoresis, and RORα and GAPDH mRNA expression was confirmed as a band. These bands were photographed with a polaroid camera and quantified using a densitometer, and the expression level of RORα mRNA was determined as a ratio to the expression level of GAPDH mRNA, which is an internal standard, and expressed as an expression ratio when the control was 1. As a result, as shown in Table 1, the compound represented by the chemical formula (1) and / or a salt thereof enhanced the expression of RORα mRNA.

Experimental Example-2 Protective effect of RORα against ultraviolet irradiation A sample was added to a normal human keratinocyte in a confluent state so as to be 10 μM. After 24 hours, the culture medium was replaced with PBS, and UVB was irradiated with 30 mJ / cm ² . Total RNA was extracted 3 hours after irradiation, and RORα mRNA expression level was measured by RT-PCR based on the total RNA. The RT-PCR method is described in TaKaRa RNA PCR Kit (AMV) Ver. 2.1 was used. GAPDH was used as an internal standard. Other operations were carried out according to a predetermined method, and the PCR reaction solution was subjected to agarose gel electrophoresis, and RORα and GAPDH mRNA expression was confirmed as a band. These bands were photographed with a polaroid camera and quantified using a densitometer, and the expression level of RORα mRNA was determined as a ratio to the expression level of GAPDH mRNA, which is an internal standard, and expressed as an expression ratio when the control was 1. As a result, as shown in Table 2, the compound represented by the chemical formula (1) and / or a salt thereof suppressed the decrease in RORα mRNA expression due to ultraviolet rays and exhibited a protective effect.

Experimental Example-3 Use Test Using the cream of Prescription Example-7 and the cream of Comparative Example-1, a use test for 2 months was conducted for 30 women (25-51 years old). After use, a questionnaire survey was conducted on the effect of improving the dryness of the skin, fine lines, dullness, and turbulence in the skin to determine the anti-aging effect. The evaluation criteria of the questionnaire were evaluated as “excellent” for valid, “good” for slightly effective, “good” for slightly effective, and “impossible” for invalid.

  These results are shown in Table 3. The composition containing the ROR activator of the present invention showed an excellent anti-aging effect on the skin. During the test period, there was no skin problem and there was no problem with safety.

  When similar tests were conducted for Formulation Examples 1 to 6 and 8 to 14, all showed safe and excellent anti-aging effects on the skin.

The compound represented by the chemical formula (1) of the present invention and / or a salt thereof has an excellent ROR activation effect on skin cells, and exhibits symptoms such as dryness, fine wrinkles, dullness, and texture disorder associated with skin aging. It can be incorporated into pharmaceuticals, quasi drugs, cosmetics or foods for the purpose of improvement.

Claims (8)

An anti-aging composition comprising a retinoid-related orphan receptor (ROR) activator. An anti-aging composition, wherein the ROR activator according to claim 1 is a compound represented by the chemical formula (1) and / or a salt thereof.

R _1, R ₂ is according to claim 1 or anti-aging composition according to any one claim of 2, wherein the hydrogen atom. The anti-aging composition according to any one of claims 1 to 3, wherein ROR is RORα or RORγ. A composition for preventing photoaging containing a ROR activator. A composition for photoaging prevention, wherein the ROR activator according to claim 5 is a compound represented by the chemical formula (1) and / or a salt thereof. R < ₁ >, R < ₂ > is a hydrogen atom, The composition for photoaging prevention as described in any one of Claim 5 or 6 characterized by the above-mentioned. ROR is ROR (alpha) or ROR (gamma), The composition for photoaging prevention as described in any one of Claims 5-7 characterized by the above-mentioned.