JP2007039394A - External preparation for skin for preventing and ameliorating aging - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a promoter of information transfer between cells by GJ (gap junction) or expression of connexin 43, or an external preparation for the skin for preventing and ameliorating aging of the skin. <P>SOLUTION: The composition contains a peptide having ≥500 and ≤2,000 molecular weight and/or a peptide including a sequence comprising Ala and Asp. A peptide of one example thereof has the amino acid sequence 1: Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

The present invention is an invention in the technical field relating to anti-aging, and in particular, a peptide having a molecular weight of 500 to 2000 and / or a peptide comprising a sequence consisting of Arg, Ala, and Asp that enhances cell-cell communication and connexin expression (hereinafter, As an example, the present invention relates to an intercellular communication enhancer and an anti-aging improvement skin external preparation containing a peptide having the following amino acid sequence 1 or a collagen peptide as an active ingredient.
Amino acid sequence 1: Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala

Cells are bound together by cell-cell adhesion. One of the cell-cell adhesions is a gap junction (hereinafter abbreviated as “GJ”). GJ not only connects adjacent cells but also participates in information transmission between cells (Non-patent Document 1). Information is transmitted by allowing molecules having a molecular weight of about 1000 Da or less to pass between adjacent cells. If this is not performed normally, abnormal functions of each tissue are caused.
It is the cell membrane protein connexin that constitutes GJ. A channel called connexon, in which six molecules of connexin are bound, associates between adjacent cells to form GJ (Non-patent Document 2). Connexins are expressed in a tissue-specific manner, and the main connexin proteins in keratinocytes are connexins 26 and 43 (Non-patent Document 3).

J. et al. E. Trosko, et al. , Life Science, 1993, 53, 1-19 Goodenough DA, et al. , Annu Rev Biochem. , 1996, 65, 475-502. Denis S, et al. , J .; Clin. Invest. , 1988, 82, 248-254.

  It has been found that the information transmission between cells via GJ and the expression level of connexin decrease with aging, and the GJ function of keratinocytes and the expression level of connexin decrease due to ultraviolet rays. Therefore, enhancement of GJ function and connexin expression prevent skin aging due to aging and ultraviolet rays, and control of GJ and connexin is considered to be effective in preventing skin aging (Non-patent Document 4). Patent Document 1).

Hiroaki I, FRAGRANCE JOURNAL, 2003, 12, 100-105 Special table 2002-541084

  There has been a demand for the development of an external preparation for skin that safely provides an excellent skin aging improvement effect without side effects.

Under such circumstances, as a result of intensive investigations aimed at suppressing skin aging, the present inventors have found that peptides having a molecular weight of 500 or more and 2000 or less and / or peptides containing a sequence consisting of Arg, Ala and Asp (RAD peptide), As an example, the present inventors have found that a peptide having the following amino acid sequence 1 or a collagen peptide exhibits a GJ function promoting action and a connexin expression enhancing action, thereby completing the present invention.
Amino acid sequence 1: Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala

  That is, since the present invention has a GJ function promoting action and a connexin expression enhancing action, skin aging and photoaging prevention and improvement effects are expected.

  The RAD peptide used in the present invention is a peptide containing a sequence consisting of three amino acids, Arg, Ala and Asp. In the use, it can synthesize | combine and utilize by a conventional method.

  Any number of amino acid residues of RAD used in the present invention can be synthesized. Among them, RAD4 (including 4 RAD sequences) to RAD16 (including 16 RAD sequences) having high skin permeability are preferable. The blending amount of RAD is not particularly limited, but is preferably 0.0001 to 5% by weight, more preferably 0.001 to 1% by weight in terms of solid content, based on the total amount of the external preparation for skin in the present invention. It is. If it is less than 0.0001% by weight, a sufficient effect is hardly exhibited. When the blending amount exceeds 5% by weight, the effect is hardly increased and it is uneconomical. In addition, the addition method may be added in advance or during the production, and may be appropriately selected in consideration of workability.

  Collagen component or gelatin component which is a starting material of collagen peptide according to the present invention is bone, skin, tendon or flounder such as cow, pig, bird, flounder, salmon, salmon, salmon, salmon, etc., bone, skin, tendon, Scales, floats, etc. can be used. Extraction and purification of the collagen component or gelatin component from these raw materials can be usually performed using a known method.

  These hydrolysiss to obtain collagen peptides can be performed using enzymes such as proteolytic enzymes. Enzymes used to prepare hydrolysates are trypsin, chymotrypsin, subtilisin, elastase, proline-specific protease, protease produced by Streptococcus microorganisms, protease produced by Aspergillus microorganisms, and Streptomyces microorganisms Proteases, proteases produced by Rhizopus microorganisms, proteases produced by Bacillus microorganisms, proteases produced by lactic acid bacteria, papain, bromelain, kukumycin, pepsin, thermolysin and the like can be used. Collagenases derived from bacteria such as Clostridium genus and Streptomyces genus, actinomycetes or fungi can also be used. Moreover, even if it is the protease produced to other microbial cells by the gene recombination technique, it is also possible to ferment with these microorganisms without a problem. Further, a plurality of enzymes may be mixed and used. Of these, proctase, promelain, papain, collagenase, pepsin and the like are preferable.

  The amount of enzyme used for hydrolysis is about 0.01% to 10%, preferably about 1% by weight with respect to the raw material, and the temperature condition is room temperature to 90 ° C., preferably 37 ° C. to 55 ° C., reaction time. Is processed for 1 to 24 hours, preferably 1 to 8 hours. The pH condition is adjusted to the optimum pH before adding the enzyme. After completion of hydrolysis, the enzyme is deactivated by heating, and after cooling, filtration, decolorization, deodorization, desalting, concentration, and drying are performed as necessary.

  The collagen peptide of the present invention can be obtained by adjusting reaction conditions such as enzyme type, concentration, and reaction time. The average molecular weight of the collagen peptide is preferably 500 to 2000, and particularly preferably 800 to 1000. As the hydrolyzate by an enzyme, a fraction having a specific molecular weight can be obtained by using a known method such as gel filtration chromatography.

  The blending amount of the collagen peptide used in the present invention is not particularly limited, but is preferably in the range of 0.0001 to 5% by weight in terms of dry matter, more preferably 0.001 to the total amount of the antiaging agent of the present invention. 1% by weight. If the blending amount is 0.0001% by weight or less, the effect of preventing and improving wrinkle formation is low, and if it exceeds 5% by weight, the effect is hardly increased and is not efficient. The addition method may be added in advance or during the production, and may be appropriately selected in consideration of workability.

  In the external preparation for skin of the present invention, fats, waxes, hydrocarbons, fatty acids, alcohols, esters, which are components used in normal cosmetics and quasi-drugs, as long as the effects of the components are not impaired , Surfactants, metal soaps, pH adjusters, preservatives, fragrances, moisturizers, powders, UV absorbers, thickeners, dyes, antioxidants, whitening agents, chelating agents, etc. You can also.

  The external preparation for skin of the present invention can be used for any of cosmetics, quasi drugs, and pharmaceuticals. Examples of the dosage form include skin lotion, cream, emulsion, gel, aerosol, essence, pack, Detergents, bath preparations, foundations, dusting powders, lipsticks, and the like.

  The intercellular communication enhancer and the anti-aging skin external preparation of the present invention enhanced intercellular communication via gap junction, enhanced the expression of connexin, and further exhibited an excellent effect in improving talmi.

  Next, in order to describe the present invention in detail, examples of production, formulation and experimental examples of peptides and extracts used in the present invention will be given as examples, but the present invention is not limited thereto. The compounding amount shown in the examples indicates% by weight.

Production Example 1 Synthesis of RAD RAD having 3 to 48 amino acid residues (RAD3 to RAD48) was synthesized by a peptide synthesizer (Applied Biosystems Peptide Synthesizer 431A) and purified by HPLC.

Production Example 2 Collagen Peptide 1 by Pepsin Hydrolysis
As collagen protein, 30 g of gelatin prepared from flounder skin was dissolved by heating in 300 mL of distilled water. 300 mg of pepsin (manufactured by Nippon Biocon Co., Ltd.) was added, the pH was adjusted to 3.5 with acid, and the mixture was allowed to stand at 50 ° C. for 1 hour. After completion of the reaction, the reaction solution was neutralized and heated at 100 ° C. for 15 minutes to deactivate the enzyme. Then, after activated carbon treatment, freeze-drying was performed to obtain a collagen peptide having an average molecular weight of 5000.

Production Example 3 Collagen Peptide 2 by Pepsin Hydrolysis
Gel filtration chromatography using Bio-Gel P-2 (manufactured by BIO-RAD) in which the activated carbon treatment solution in Production Example 1 was equilibrated with distilled water was performed, and the fractions having an average molecular weight of 280, 500, and 1000 were lyophilized. did.

Production Example 4 Collagen Peptide 3 by Papain Hydrolysis
As collagen protein, 30 g of gelatin prepared from scab was dissolved by heating in 300 mL of distilled water. Papain (manufactured by Amano Enzyme) (300 mg) was added, the pH was adjusted to 7.0 with aqueous ammonia, and the mixture was allowed to stand at 50 ° C. for 1 hour. After completion of the reaction, the reaction solution was heated at 100 ° C. for 15 minutes to deactivate the enzyme. Then, after activated carbon treatment, freeze-drying was performed to obtain a collagen peptide having an average molecular weight of 10,000.

Production Example 5 Collagen Peptide 4 by Papain Hydrolysis
Gel filtration chromatography using Bio-Gel P-2 (manufactured by BIO-RAD) in which the activated carbon treatment solution of Production Example 4 was equilibrated with distilled water was performed, and fractions having an average molecular weight of 500 and 2000 were lyophilized.

Production Example 6 Collagen Peptide 5 by Collagenase Hydrolysis
As collagen protein, 30 g of gelatin prepared from cocoon scale was dissolved by heating in 300 mL of distilled water. 300 mg of collagenase type I (manufactured by Worthington Biochemical Corp) was added, the pH was adjusted to 7.5 with aqueous ammonia, and the mixture was allowed to stand at 37 ° C. for 1 hour. After completion of the reaction, the reaction solution was heated at 100 ° C. for 15 minutes to deactivate the enzyme. Then, after activated carbon treatment, freeze-drying was performed to obtain a collagen peptide having an average molecular weight of 1000.

Production Example 7 Collagen Peptide 6 by Collagenase Hydrolysis
Gel filtration chromatography using Bio-Gel P-2 (manufactured by BIO-RAD) in which the activated carbon treatment solution of Production Example 6 was equilibrated with distilled water was performed, and a fraction having an average molecular weight of 400 was freeze-dried.

Production Example 8 Collagen peptide 7 produced by protease hydrolysis produced by Papain and Bacillus microorganisms
As collagen protein, 30 g of gelatin prepared from flounder skin was dissolved by heating in 300 mL of distilled water. 300 mg each of papain (manufactured by Amano Enzyme) and protease produced by a microorganism belonging to the genus Bacillus (manufactured by Amano Enzyme) were added, adjusted to pH 7.5 with aqueous ammonia, and allowed to stand at 50 ° C. for 3 hours. After completion of the reaction, the reaction solution was heated at 100 ° C. for 15 minutes to deactivate the enzyme. Subsequently, after activated carbon treatment, freeze-drying was performed to obtain a collagen peptide having an average molecular weight of 3000.

Production Example 9 Collagen Peptide 8 Protease Hydrolyzed Produced by Papain and Bacillus Microorganisms 8
Gel filtration chromatography using Bio-Gel P-2 (manufactured by BIO-RAD) in which the activated carbon treatment solution of Production Example 7 was equilibrated with distilled water was performed, and a fraction having an average molecular weight of 800 was freeze-dried.

Formulation Example 1 Cream 1
Formulation Formulation 1. RAD16 0.5 part2. 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 3 to 10 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, 2 and 12-15 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 11 is added at 45 ° C., and further cooled to 30 ° C. to obtain a product.

Formulation Example 2 Cream 2
In Formulation Example 1, Cream 2 was prepared by replacing 1 RAD16 with a collagen peptide (average molecular weight 500, Production Example 3).

Comparative Example 1 Conventional cream 1
In Formulation Example 1, a conventional cream 1 was prepared by replacing 1 with purified water.

Formulation Example 3 Lotion Formulation Amount Collagen peptide (average molecular weight 1000, Production Example 5) 1.0 part 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. Bring the total amount to 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 4 Emulsion Formulation Formulation 1. RAD12 0.2 part2. 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 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 11-13 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 10 is added at 45 ° C., and further cooled to 30 ° C. to obtain a product.

Formulation Example 5 Gel formulation Formulation amount 1. RAD8 1.0 part
2. Ethanol 5.0
3. Methyl paraoxybenzoate 0.1
4). Polyoxyethylene hydrogenated castor oil (60 EO) 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. [Production method] Ingredients 1 to 5 and 6 to 11 are uniformly dissolved in purified water to 100, and both are mixed to obtain a product.

Formulation Example 6 Pack Formulation Amount RAD10 0.001 part2. Polyvinyl alcohol 12.0
3. Ethanol 5.0
4.1,3-Butylene glycol 8.0
5. Methyl paraoxybenzoate 0.2
6). Polyoxyethylene 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 Formulation Amount RAD7 0.1 part
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 a total amount of 100, 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, and the mixture is stirred with a homomixer and kept at 75 ° C. to obtain an aqueous phase. The oily phase is added to the aqueous phase while stirring, cooled, and component 19 is added at 45 ° C, and cooled to 30 ° C while stirring to obtain a product.

Formulation Example 8 Bath preparation formulation RAD18 0.001 part2. Sodium bicarbonate 50
3. Yellow No. 202 (1) Appropriate amount 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 Evaluation of RAD's Skin Retention Effect RAD's skin retention effect was evaluated using the Franz diffusion cell method, which is a typical method for evaluating skin permeability. That is, Yucatan Micropig skin was attached to a Franz diffusion cell, 500 μL of a 2% RAD aqueous solution was added to the donor phase, and sealed with parafilm. To the receiver phase, physiological saline supplemented with 100 U / mL penicillin G and 100 μg / mL streptomycin was added and stirred at 37 ° C. to allow RAD to permeate the skin for 12 hours. Thereafter, the RAD aqueous solution in the donor phase was replaced with physiological saline, and further stirred for 24 hours. Skin retention was calculated by comparing the amount of collagen peptide permeated by stirring for 12 hours and the amount of RAD retained in the skin 24 hours after removal. As a result, as shown in Table 1, an excellent skin retention effect was observed for RAD having a molecular weight of about 500 to 1700.

Experimental Example 2 Cell-cell communication enhancement effect Evaluation of cell-cell communication by GJ was evaluated by the Scrap-loading and dye transfer (SLDT) method (JU Park, et al., J Biome Mater Res.,). 2002, 60, 541-547). First, human keratinocyte-derived cell line HaCaT cells are cultured in 10% fetal bovine serum-containing DMEM medium (hereinafter referred to as medium). When confluent, RAD16 of amino acid sequence 1 has a final concentration of 0.001, The collagen peptide was added to the medium so as to be 0.01, 0.1% or 1%. Seven days after the addition of RAD16 and collagen peptide, a line is drawn with a 27G injection needle on the surface on which the petri dish cells are cultured, and the wound is made. Then, it culture | cultivated for 5 minutes on 37 degreeC and 5% CO2 conditions in the culture medium which added Lucifer yellow so that it might become 0.1%. The medium was removed, the cells were washed 3 times with PBS, and lucifer yellow uptake was measured with a fluorescence microscope. That is, when the intercellular communication is developed, a lot of lucifer yellow is taken up. As a result, as shown in Table 2, the addition of RAD16 increased the uptake of lucifer yellow.
Amino acid sequence 1: Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala

Experimental Example 3 Protein Expression Enhancement Effect of Connexin 43 When HaCaT cells are confluent, the final concentration of RAD16 is 0.001, 0.01, 0.1%, or the collagen peptide is 1%. To the medium. Seven days after the addition of RAD16, the medium was removed, the cells were washed twice with PBS, and the total protein was extracted. 20 μg of this protein was subjected to SDS polyacrylamide gel electrophoresis and then blotted on a transfer membrane (Millipore). After completion of blotting, Contixin 43 using Anti-Connexin 43 Polyantibody (Zymed) as the primary antibody, Anti-Rabbit IgG HRP-Linked antibody (Amersham) as the secondary antibody, and ECL Western blotting detection reagent (Amersham) as the detection reagent. Protein was detected as a band. These bands were quantified with a densitometer. In this example, the synthesis acceleration rate was calculated by the following formula using the numerical value of the densitometer used. As a result, as shown in Table 3, RAD16 and the collagen peptide showed an effect of promoting the synthesis of connexin 43 protein in all proteins.

Synthesis promotion rate (%) = A / B × 100
A: Densitometer value when sample is added B: Densitometer value when sample is not added

Experimental Example 4 Connexin 43 protein protective effect against UV irradiation With HaCaT cells confluent, the final concentration of RAD16 is 0.001, 0.01, 0.1%, or collagen peptide is 1% Was added to the medium. Seven days after the addition of RAD16, the culture medium was replaced with PBS, and UVB was irradiated with 25 mJ / cm ² . Immediately after the irradiation, PBS was replaced with the medium again, and the total protein was extracted 24 hours later. 20 μg of this protein was subjected to SDS polyacrylamide gel electrophoresis and then blotted on a transfer membrane (Millipore). After completion of blotting, Contixin 43 using Anti-Connexin 43 Polyantibody (Zymed) as the primary antibody, Anti-Rabbit IgG HRP-Linked antibody (Amersham) as the secondary antibody, and ECL Western blotting detection reagent (Amersham) as the detection reagent. Protein was detected as a band. These bands were quantified with a densitometer. In this example, the synthesis acceleration rate was calculated by the following formula using the numerical value of the densitometer used. As a result, as shown in Table 4, RAD16 suppressed the decrease in the expression of connexin 43 protein due to ultraviolet rays.

  Regarding connexin 26 and connexin 32, the effect of enhancing expression by RAD16 and collagen peptide was also observed. In addition to RAD16, RAD3-48 also showed an effect of enhancing connexin expression.

Experimental Example 5 Evaluation of Anti-Aging Action A control group and a RAD16 administration group were prepared for 5 males and 30s of 30-week-old aging-promoting mice (SAM P10). In the control group, physiological saline was administered, and in the RAD16 administration group, RAD16 dissolved in physiological saline so as to be 0.1% was administered into the back and skin of the mice shaved with clippers. One week after administration, the dorsal skin of the clipped mouse was pinched between the thumb and forefinger and immediately released, and the number of seconds for restoring the skin wrinkles was measured. As a result, as shown in Table 5, the restoration time was significantly shorter in the RAD16 administration group than in the control group.

Experimental Example 6 Talmi Improvement Effect 1 for 20 women (25 to 40 years old) suffering from skin tarmi using Cream 1 of Formulation Example 1, Cream 2 of Formulation Example 2 and conventional cream of Comparative Example 1 Monthly use test was conducted. After use, the effect of improving skin talmi was evaluated by a questionnaire.

  These results are shown in Table 6. As a result, the skin external preparation characterized by containing RAD16 showed an excellent talmi improving effect.

  All the external preparations for skin obtained in Formulation Examples 3 to 8 showed a sufficient improvement effect in talmi. Moreover, there was no skin trouble and it was safe.

As an application example of the present invention, it can be used in any of cosmetics, quasi-drugs, and pharmaceuticals, and an effect of improving skin aging resulting from a decrease in intercellular communication function can be obtained.

Claims (9)

A cell-cell communication enhancer comprising a peptide having a molecular weight of 500 or more and 2000 or less. A cell-cell communication enhancer comprising a peptide comprising a sequence consisting of Arg, Ala and Asp (hereinafter collectively referred to as RAD peptide). An intercellular communication enhancer comprising a RAD peptide having a molecular weight of 500 or more and 2000 or less. A cell-cell communication enhancer comprising a peptide having the following amino acid sequence 1:
Amino acid sequence 1: Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala A cell-cell communication enhancer comprising a collagen peptide having an average molecular weight of 500 or more and 2000 or less. The intercellular communication enhancer according to any one of claims 1 to 4, wherein the enhancement of intercellular communication is due to enhancement of a gap junction function. The intercellular communication enhancer according to any one of claims 1 to 6, which enhances the expression of connexin. An anti-aging skin external preparation containing the intercellular communication enhancer according to any one of claims 1 to 7. The photoaging prevention skin external preparation containing the intercellular communication enhancer as described in any one of Claims 1-8.