JP2006232769A - Ceramide synthesis promoter - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a ceramide synthesis promoter having excellent prophylactic or ameliorating effects on skin roughening or dry skin and to provide a composition comprising the promoter formulated therein. <P>SOLUTION: A compound represented by chemical formula (1) (wherein, R<SB>1</SB>and R<SB>2</SB>are each selected from a hydrogen, an alkyl group, an aryl group, an acyl group and ethylene acetate) and/or a salt thereof have excellent promoting effects on ceramide synthesis. A composition comprising the compound formulated therein is safe and has excellent prophylactic or ameliorating effects on skin roughening and dry skin. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a ceramide synthesis accelerator characterized by containing a compound represented by the chemical formula (1) and / or a salt thereof, and particularly to a composition effective for preventing rough skin and dry skin.

  Ceramide is the main component of lamellar granules produced and secreted in the upper spiny layer and granule layer when cells move from the basal layer of the skin to the stratum corneum. Forms keratinocyte lipids that play an important role. Causes of rough skin include dryness, contact with irritants, and skin irritation due to ultraviolet rays. It is said that promoting the production of ceramide is effective in restoring the barrier function that protects the skin from dryness and irritants. It has been confirmed that seven types of ceramide are present in human skin, and it is ideal to supplement all types of ceramide with the ratio existing in the stratum corneum.

Conventionally, ceramide has been blended into various skin external preparations as a cosmetic that is effective in preventing and improving rough skin and dry skin, but supplements all types of ceramide present in human skin at an appropriate ratio. That was technically difficult. Therefore, it is considered important to promote ceramide synthesis in vivo. Patent Documents 1 and 2 have been reported as ceramide synthesis accelerators. The ceramide synthesis promoting effect of the compound represented by the chemical formula (1) and / or a salt thereof has not been reported.
JP-A-8-217658 JP 2001-220345 A

  From the above, a ceramide synthesis accelerator excellent in the effect of improving rough skin and dry skin is desired.

  Under such circumstances, the present inventors have intensively studied and found that the synthesis of ceramide is promoted by the compound represented by the chemical formula (1) and / or a salt thereof, and a composition containing them. The present inventors have found an effect of preventing and improving rough skin and dry skin, and have completed the present invention.

That is, the present invention is a ceramide synthesis accelerator characterized by containing a compound represented by the chemical formula (1) and / or a salt thereof. R ₁ and R ₂ are each selected from hydrogen, an alkyl group, an aryl group, an acyl group, and ethylene oxide.

The compounds represented by the chemical formula (1) of the present invention and / or their salts can be naturally derived or synthesized from commercially available tocopherols by a conventional method. it can.
JP-B 61-20583 JP 3-32558

  In the present invention, the salt of 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. In particular, dl-α-tocopheryl phosphate disodium, which is a sodium salt, is commercially available and can be used.

  In order to use the ceramide synthesis promoter characterized by blending the compound represented by the chemical formula (1) of the present invention and / or a salt thereof for the purpose of improving rough skin, it is usually used systemically or locally. Administered by topical use. The dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually 1 mg to 1 g per adult, preferably 20 mg to 200 mg once to several times a day. Is done. Since the dosage varies depending on various conditions, an amount smaller than the above-mentioned administration range may be sufficient, or it may be necessary to administer beyond the range.

  As the ceramide synthesis promoter for oral administration of the present invention, it can be used for any of foods, quasi drugs and pharmaceuticals, tablets, pills, powders, granules, capsules, emulsions, solutions Agents, suspensions, syrups, elixirs and the like. The above compounds may be used as they are and within the range not impairing the effects of the present invention, excipients, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffering agents. Perfumes, preservatives, solubilizers, solvents and the like can be used. Specifically, lactose, sucrose, sorbit, mannitol, starch, precipitated calcium carbonate, heavy magnesium oxide, talc, calcium stearate, magnesium stearate, cellulose or derivatives thereof, amylopectin, polyvinyl alcohol, gelatin, surface activity Agents, water, physiological saline, ethanol, glycerin, propylene glycol, cacao butter, lauric fat, petrolatum, paraffin, higher alcohol and the like.

  The ceramide synthesis promoter for external use of the present invention can be used in any of cosmetics, quasi drugs and pharmaceuticals. Examples of the dosage form thereof include lotions, creams, emulsions, gels, and aerosols. , Essences, packs, cleaning agents, bath preparations, foundations, dusting powders, lipsticks, ointments, poultices, and the like. The above compounds may be used as they are and within the range not impairing the effects of the present invention, oils and fats, waxes, hydrocarbons, fatty acids, alcohols, esters, surfactants, which are components used for external preparations Components such as an agent, a metal soap, a pH adjuster, an antiseptic, a fragrance, a moisturizer, a powder, an ultraviolet absorber, a thickener, a pigment, an antioxidant, a whitening agent, and a chelating agent can also be blended.

  The amount of the compound blended in the ceramide production promoter 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 compound represented by the chemical formula (1) of the present invention and / or a salt thereof was excellent in the ceramide synthesis promoting effect. Moreover, the composition containing these compounds was safe and rough, and was excellent in the effect of improving dry skin.

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

  The compound represented by the chemical formula (1) of the present invention and / or a salt thereof can be formulated as the following formulation examples.

Formulation Example 1 Cream Formulation 1. dl-α-tocopheryl sodium phosphate 2.0% by weight
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 [Manufacturing method] Components 2 to 9 are heated and dissolved and mixed with purified water to a total amount of 100, 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.

Comparative Example 1 Conventional Cream In Formulation Example 1, a conventional cream was prepared by replacing dl-α-tocopheryl phosphate with purified water.

Formulation Example 2 Lotion amount 1. d-α-Tocopheryl sodium phosphate 0.1% by weight
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. [Manufacturing method] Components 1 to 6 and 11 and components 7 to 10 are uniformly dissolved in purified water, and both are mixed and filtered to obtain a product.

Formulation Example 3 Emulsion Formulation Amount 1. dl-α-Tocopheryl phosphate disodium 0.5% by weight
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. [Manufacturing method] Components 2 to 8 are heated and dissolved and mixed with purified water to a total amount of 100, 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 4 Gel formulation d-α-Tocopheryl potassium phosphate 0.1% by weight
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. [Manufacturing method] Components 2 to 5 and components 1 and 6 to 11 are uniformly dissolved in purified water, and the two are mixed to obtain a product.

Formulation Example 5 Ointment Formulation 1. dl-α-Tocopheryl sodium phosphate 1.0% by weight
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). [Manufacturing method] Components 2-5 are heated and dissolved and mixed with purified water to 100, 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 6 Pack Blending amount 1. dl-α-Tocopheryl potassium phosphate 0.1% by weight
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. [Production method] Components 1 to 10 are uniformly dissolved in purified water to give a product of 100.

Formulation Example 7 Foundation d-α-Tocopheryl phosphate disodium 1.0% by weight
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. [Manufacturing method] Components 2 to 9 are heated and dissolved in purified water to make the total amount 100, and kept at 80 ° C to obtain an oil phase. Ingredient 20 is well swollen with ingredient 10, then ingredients 1 and 11-14 are added and mixed 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 8 Bath preparation amount dl-α-Tocopheryl sodium phosphate 1.0% by weight
2. Sodium bicarbonate 50.0
3. Yellow 202 No. 4 Perfume appropriate amount 5. [Production method] Ingredients 1-5 are uniformly mixed with anhydrous sodium sulfate to make a total amount of 100 to obtain a product.

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

Experimental Example 1 Ceramide Synthesis Promotion Test 1 × 10 ⁵ Pam212 cells, a mouse keratinocyte-derived cell line, were seeded in a 6 cm dish and cultured for 4 days. Thereafter, the sample was added to a final concentration of 5 μM, and the culture was further continued for 24 hours. Next, the cells were washed three times with PBS (−), collected by a rubber policeman, and lyophilized. Lipids were extracted from cells with 1 mL of chloroform: methanol (2: 1), and the amount of ceramide in the cells was determined by the fluorescence method of Kisic et al. (Kisic A. and Rapport MM, Journal of Lipid Research, 15, 179-180. (1974)). That is, the lipid was hydrolyzed with 0.15 mL of 3N hydrochloric acid at 100 ° C. for 2 hours, dried in a desiccator, removed with hydrochloric acid, and then added with 2 mL of ethyl acetate and 1.25 mL of 0.1 M acetate buffer (pH 3.7). Stir well. Next, 0.25 mL of a fluorescamine solution (fluorescamine 7 mg / 25 mL acetone) was added, stirred well, then centrifuged, and the fluorescence intensity of the ethyl acetate layer was measured at Ex 410 nm and Em 490 nm. The amount of ceramide synthesis with no sample added was taken as a control, and the value of the amount of ceramide synthesized when the sample was added when the control was 100 was taken as the ceramide synthesis rate.

  The results of these experiments are shown in Table 1. As a result, the compound represented by the chemical formula (1) and / or a salt thereof showed an excellent ceramide synthesis promoting effect as compared with the control.

Experimental Example 2 Use Test Using the cream of Prescription Example 1 and the cream of Comparative Example 1, a use test for one month was conducted on 30 women (18 to 50 years old) who suffer from rough skin and dry skin. After use, the improvement effect of rough skin and dry skin was determined by questionnaire.

  The test results are shown in Table 2. As a result, the cream obtained in Formulation Example 1 was superior to the conventional cream obtained in Comparative Example 1 in preventing and improving rough skin and dry skin. During the test period, there was no skin problem and there was no problem with safety.

  When the same use test was done about the formulation examples 2-8, all showed the anti-aging effect of the skin which was safe and excellent.

The compound represented by the chemical formula (1) of the present invention and / or a salt thereof can be used as an excellent ceramide synthesis accelerator. In addition, it can be blended into pharmaceuticals, quasi drugs, cosmetics or foods for the purpose of improving safety, rough skin and dry skin.

Claims (3)

A ceramide synthesis accelerator comprising a compound represented by the chemical formula (1) and / or a salt thereof.

The ceramide synthesis accelerator according to claim ₁ , wherein R ₁ and R ₂ are hydrogen atoms. A composition excellent in the effect of preventing or improving rough skin and dry skin, comprising the ceramide synthesis promoter according to claim 1.