JP3522609B2 - Hyaluronic acid production promoter and skin external preparation containing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention has an action of promoting hyaluronic acid production of skin fibroblasts, and is useful for prevention of skin aging, promotion of wound healing, or treatment of diseases accompanied by abnormal decomposition of hyaluronic acid. Ru <br/> relates to a hyaluronic acid production-promoting agent. More specifically, cell medical yarrow (Achillea
relates to one or hyaluronic acid production promoting agent comprising two or more flower extract millefolium L.).

[0002]

2. Description of the Related Art Hyaluronic acid is a linear polymer polysaccharide formed by alternately binding DN-acetylglucosamine and D-glucuronic acid, and constructs an extracellular matrix with collagen, fibronectin and proteoglycan. It has many functions such as cell retention, tissue lubricity retention, resistance to external forces such as physical injury, and bacterial infection prevention. It is known that, particularly in the skin dermis, it is produced by fibroblasts and is involved in the elasticity maintenance of the skin and the healing process of wounds. It is also known that cell adhesion and cell migration are controlled via specific receptors.

[0003] Degradation of hyaluronic acid due to various external stresses such as aging and exposure to ultraviolet rays and a decrease in hyaluronic acid producing ability of fibroblasts lead to the progression of skin aging symptoms such as a decrease in skin elasticity and wrinkle formation. It is thought to contribute to the delay of wound healing. Also, in diseases such as rheumatoid arthritis, purulent arthritis, gouty arthritis, traumatic arthritis, osteoarthritis, and osteoarthritis, abnormal degradation of hyaluronic acid is observed. Therefore, attempts have been made to externally supplement hyaluronic acid in the prevention and improvement of such skin aging symptoms, promotion of wound healing, or treatment of diseases associated with abnormal decomposition of hyaluronic acid.

In the field of external preparations for skin, many attempts have been made to apply hyaluronic acid or a salt thereof to an external preparation base (Japanese Patent Publication No. 60-19725, 61-381).
68, 62-53484, etc.), joint injection therapy of hyaluronic acid is performed in the treatment of the above-mentioned diseases accompanied by abnormal decomposition of hyaluronic acid. However, regarding the application of the skin external preparation containing hyaluronic acid, hyaluronic acid is a high-molecular-weight polysaccharide and is difficult to be percutaneously absorbed.
There is a problem that hyaluronic acid is decomposed with time and the viscosity of the external preparation for skin is lowered. In addition, joint injection therapy of hyaluronic acid requires long-term treatment,
Since it requires a doctor's prescription, there is a problem that it is not suitable for daily treatment.

Therefore, in the external preparation for skin, the viscosity of hyaluronic acid is suppressed from being lowered to improve the stability of the preparation (Japanese Patent Publication No. 1-7043, 1-10485, etc.), or low-molecular weight hyaluronic acid is used (patented) No. 2549119),
Derivatives of hyaluronic acid are also used (Patent No. 2569)
No. 012, No. 2604930, No. 2648308
Other than these attempts, many attempts to promote the production of hyaluronic acid in the living body or inhibit the activity of hyaluronidase to suppress the decomposition of hyaluronic acid have been disclosed.

As such hyaluronic acid production promoter,
Extracts of seaweeds such as the genus Ulva, the genus Aonori, the genus Funori and the genus Darbiri, etc.
101871, ibid 8-198741, ibid 9-17603
6), plant extracts such as Mesoi, Regulo, Lamiaceae plants, etc. (JP-A-9-87163, 10-29922, 10-9)
5735), yeast extract (JP-A-8-163983),
Fraction of bovine serum having a molecular weight of 5,000 or less (Japanese Patent Application Laid-Open No. 8-23
9404) and the like are disclosed. On the other hand, as a hyaluronidase inhibitor, one containing an extract of button and peony (JP-A-1-128933) and one containing rosmarinic acid as an active ingredient (JP-A-9-6725).
1) etc. are disclosed.

However, the conventional hyaluronic acid production promoters and hyaluronidase inhibitors as described above are insufficient in hyaluronic acid production promoting effect or hyaluronidase inhibitory effect, quality, stability or safety. In fact, there is a need for a novel hyaluronan production-promoting activity.

[0008]

Therefore, in the present invention, a hyaluronic acid production promoter having an excellent hyaluronic acid production promoting action on fibroblasts, good stability and safety, and suitable for external use is also provided. And further applying it to provide a skin external preparation useful for preventing and improving skin aging symptoms, promoting wound healing, and treating diseases associated with abnormal decomposition of hyaluronic acid.

[0009]

To solve the above problems SUMMARY OF THE INVENTION, it was subjected to screening for substances that enhance hyaluronic acid production ability of fibroblasts without exhibiting cytotoxicity, cell medical yarrow (Achillea millefolium
A high hyaluronic acid production promoting activity was found in the L.) flower extract, and the present invention was completed by using the extract.

[0010] That is, in the present invention, one or more flower extracts of cell medical yarrow (Achillea millefolium L.), as it is or be contained in a carrier or base to the hyaluronic acid production-promoting agent It

[0011]

Rousset medical yarrow used as a starting material in obtaining hyaluronic acid production-promoting agent according to the embodiment of the present invention (Achillea millefolium L.) is Asteraceae (Composi
tae ) is a perennial herb that is wild in North America and Europe and is cultivated for ornamental use in Japan. In the present invention, a flower part called "Yarrow flower" is used.

These may be subjected to the extraction operation as they are, but in consideration of extraction efficiency, it is preferable to carry out the extraction after performing processing such as shredding, drying and crushing. The extraction is performed by immersing it in an extraction solvent. It may be stirred or homogenized in an extraction solvent in order to improve the extraction efficiency. As the extraction temperature, it is appropriate to set the temperature to about 5 ° C. to a temperature not higher than the boiling point of the extraction solvent. The extraction time varies depending on the type of extraction solvent and the extraction temperature, but it is suitable to be about 4 hours to 14 days.

As the extraction solvent, in addition to water, methanol,
Lower alcohols such as ethanol, propanol and isopropanol, polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, dipropylene glycol and glycerin, ethers such as ethyl ether and propyl ether, esters such as ethyl acetate and butyl acetate. A polar organic solvent such as ketones such as acetone, ethyl methyl ketone, etc. is preferably used, and one or more kinds of these are selected and used. Alternatively, physiological saline, phosphate buffer, phosphate buffered saline, etc. may be used.

[0014] The extract of the flowers of Dokudami and Achillea millefolium with the above solvent can be used as it is as a hyaluronic acid production promoter, but the concentrated and dried product can be redissolved in water or a polar solvent, or hyaluronic acid. It may be used after purification or fractionation treatment such as decolorization, deodorization, desalting, etc. within a range not impairing the acid production promoting action. For storage, it is preferable to freeze-dry after purification and dissolve in a solvent before use. In the present invention, the hyaluronic acid production promoter is used as it is, or the extract obtained from the flowers of Centella asiatica and Yarrow, or the treated product is contained in a base such as water, an aqueous carrier such as alcohol, an emulsion, a gel, a cream, an ointment or the like. And It can also be encapsulated in vesicles such as liposomes or microcapsules.

[0015]

[0016]

[0017]

EXAMPLES The features of the present invention will be described in more detail with reference to examples.

[Example 1] Hyaluronic acid production promoter 1 500 g of a dry powder of whole aerial parts of Houttuynia cordata Thunb.
It was immersed in 000 ml and left standing at 25 ° C. for 7 days. Thereafter, the plant powder was removed by filtration to obtain hyaluronic acid production promoter 1.

[Example 2] Hyaluronic acid production promoter 2 500 g of flowers of Achillea millefolium L. were added to 1,500 m of 50% by volume aqueous ethanol solution.
It was crushed in 1 l and extracted by stirring at 25 ° C. for 7 days. Thereafter, the crushed pieces of the plant were removed by filtration to obtain a hyaluronic acid production promoter 2.

The effects of the hyaluronic acid production promoters of Examples 1 and 2 of the present invention on the hyaluronic acid production ability of normal human fibroblasts were examined. That is, normal human fibroblasts were seeded on a 96-well microplate at 2.0 × 10 ⁴ cells per well, and 0.5 vol% cow containing Example 1 or Example 2 at each test concentration. After culturing in Talbecco's modified basal medium (DMEM) supplemented with fetal serum for 5 days, the amount of hyaluronic acid in the culture supernatant was measured by enzyme-linked im
It was measured by a munosorbent assay (ELISA). At the same time, the number of fibroblasts was measured, the amount of hyaluronic acid produced per cell was calculated, and the hyaluronic acid production index in which the amount of hyaluronic acid produced in the control containing no sample was 100 was shown in Tables 1 and 2. .

[0021]

[Table 1]

As shown in Table 1, the hyaluronic acid production promoter 1 according to Example 1 of the present invention is 7.5 to 5
A concentration of 0 μg / ml significantly promotes the production of hyaluronic acid in fibroblasts (risk rate 5%), 12.5 to 50 μg / m
In the case of 1, the production promoting effect was maximum (about 200%).

[0023]

[Table 2]

Further, as shown in Table 2, the hyaluronic acid production promoter 2 according to Example 2 of the present invention was 7.5
〜12.5μg / ml concentration range significantly promotes hyaluronic acid production of fibroblasts (risk rate 5%) 12.5μ
In g / ml, the above-mentioned production promoting effect is maximum (about 130
%). No cytotoxicity was observed in the concentration range tested for both Example 1 and Example 2.

Further, other examples of the hyaluronic acid production promoter according to the present invention will be shown.

Example 3 Hyaluronic Acid Production Promoter 3 Olive oil (10 g) was added to a 10% by weight gelatin aqueous solution (30 g).
Disperse and emulsify at 40 ° C. with stirring to form an O / W type emulsion. To this emulsion, add 4
30 g of 10% by weight aqueous gum arabic solution heated to 0 ° C
Are mixed with stirring. Furthermore, add 40 ° C to this mixture.
Warm water (140 ml) is added, and then acetic acid is added little by little to adjust the pH to 4.0 to form coacervate drops.
The system was cooled to 5 ° C to coagulate the coacervate droplets, 1 ml of a 10% by weight glutaraldehyde aqueous solution was added, and the pH was adjusted to 9.0 with an aqueous sodium hydroxide solution. Raise the temperature. The produced gelatin-gum arabic microcapsules were recovered by centrifugation, olive oil was extracted with acetone, and then classified by sieving in acetone, and the acetone was evaporated to immerse it in water to hydrate it. Next, hydrous gelatin-
The gum arabic microcapsules were immersed in an extract of the above-ground whole plant of Dodami, which was prepared in Example 1, with an aqueous 50% by volume ethanol solution, and gelatin-gum arabic gum microcapsules containing the same were prepared and centrifuged. And was designated as hyaluronic acid production promoter 3.

Example 4 Hyaluronic Acid Production Promoter 4 The extract of Achillea millefolium flower prepared in Example 2 above was concentrated under reduced pressure to dryness, and then dissolved in 10 ml of 50% by volume ethanol, and 100 ml of this was extracted. Add to the purified water and dissolve. To this, add 80 g of soybean lecithin and add 65
Suspension at ℃, ultrasonic treatment to prepare liposomes, collected by centrifugation and hyaluronic acid production promoter 4
And

Example 5 Hyaluronic Acid Production Promoter 5 500 g of ground cut whole grass of Houttuynia cordata Thunb. Was immersed in 2,000 ml of a 30% by volume aqueous 1,3-butylene glycol solution. After stirring and extraction at 20 ° C. for 5 days, the filtrate was collected by filtration and concentrated to 500 ml to obtain hyaluronic acid production promoter 5.

Example 6 Hyaluronic Acid Production Promoter 6 500 g of a dry crushed flower of Achillea millefolium L. was treated with 1,2-pentanediol 1,0
After immersing in 00 ml and stirring and extracting at 20 ° C. for 5 days,
The filtrate was collected by filtration and concentrated to 250 ml. This was dissolved in purified water and the total amount was adjusted to 1,000 ml to obtain hyaluronic acid production promoter 6.

[Example 7] Hyaluronic acid production promoter 7 500 g of the whole aerial part of Houttuynia cordata Thunb. Then
The supernatant is collected and lyophilized to give a hyaluronic acid production promoter 7
And

[Example 8] Hyaluronic acid production promoter 8 500 g of flowers of Achillea millefolium L. were homogenized in 2,000 ml of phosphate-buffered saline, and the mixture was stirred at 10 ° C for 24 hours and then centrifuged. After separation, the supernatant was collected and freeze-dried to obtain Hyaluronic Acid Production Promoter 8.

Next, the formulations of the examples of the external preparation for skin according to the present invention will be shown.

[0033]   [Example 9] Lotion for skin (1) Ethanol 10.0 (wt%) (2) Hydroxyethyl cellulose 1.0 (3) Hyaluronic acid production promoter 1 0.5 (4) Methyl paraoxybenzoate 0.1 (5) Purified water 88.4 Manufacturing method: (1) to (4) are sequentially added to (5) and dissolved uniformly.

Example 10 Skin Emulsion (1) Stearic Acid 0.20 (wt%) (2) Cetanol 1.50 (3) Vaseline 3.00 (4) Liquid Paraffin 7.00 (5) Polyoxy Ethylene (10 E.O.) monooleic acid 1.50 Ester (6) Tocopherol acetate 0.50 (7) Glycerin 5.00 (8) Methyl paraoxybenzoate 0.10 (9) Potassium hydroxide 0.02 (10 ) Purified water 80.18 (11) Hyaluronic acid production promoter 2 1.00 Production method: The oil phase components (1) to (6) are mixed and heated to uniformly dissolve them to 70 ° C. On the other hand, the aqueous phase components (7) to (10) are mixed and heated to homogenize the mixture to 70 ° C. The oil phase component is gradually added to this water phase component while stirring to emulsify, and after cooling, (11) is added and mixed at 40 ° C.

Example 11 Skin Gel Agent (1) Dipropylene Glycol 10.0 (wt%) (2) Carboxyvinyl Polymer 0.5 (3) Potassium Hydroxide 0.1 (4) Methyl Paraoxybenzoate 0.1 (5) Purified water 86.8 (6) Hyaluronic acid production promoter 3 2.5 Manufacturing method: (2) is uniformly dissolved in (5), then (4) is dissolved in (1). Then, (3) is added to increase the viscosity, and (6) is added and dispersed.

Example 12 Skin Cream (1) Beeswax 6.0 (wt%) (2) Cetanol 5.0 (3) Reduced Lanolin 8.0 (4) Squalane 27.5 (5) Glyceryl Fatty Acid Ester 4.0 (6) Lipophilic glyceryl monostearate 2.0 (7) Polyoxyethylene (20E.O.) sorbitan 5.0 Monolaurate (8) Propylene glycol 5.0 (9) Hyaluronic acid production Accelerator 5 3.0 (10) Methyl paraoxybenzoate 0.1 (11) Purified water 34.4 Production method: Mix and dissolve the oil phase components (1) to (7) to 75 ° C. On the other hand, mix and dissolve the water phase components (8) to (11) to 75
Heat to ℃. Next, the oil phase component is added to this aqueous phase component to pre-emulsify it, then homogenize with a homomixer and cool.

Example 13 Skin Liposomal Agent (1) Glycerin 2.0 (wt%) (2) 1,3-Butylene Glycol 3.0 (3) Polyoxyethylene (25 E.O.) Oleyl Ether 0 .2 (4) Ethanol 10.0 (5) Methyl paraoxybenzoate 0.1 (6) Perfume 0.1 (7) Purified water 74.6 (8) Hyaluronic acid production promoter 4 10.0 Production method: (5 ) And (6) are dissolved in (4), added to (7) together with (1) to (3) and mixed uniformly, and (8) is added to this and dispersed.

Example 14 Oil-in-Water Emulsion Ointment (1) White Vaseline 25.0 (wt%) (2) Stearyl Alcohol 25.0 (3) Glycerin 12.0 (4) Sodium Lauryl Sulfate 1.0 (5) Hyaluronic acid production promoter 6 1.5 (6) Hyaluronic acid production promoter 7 0.2 (7) Methyl paraoxybenzoate 0.1 (8) Purified water 35.2 Process: (1) to (4) The oil phase component of 1) is mixed and heated to dissolve uniformly, and the temperature is adjusted to 75 ° C. On the other hand, mix the water phase components (5) to (8),
Heat to homogeneity to 75 ° C. The oil phase component is gradually added to this water phase component while stirring to emulsify and cool.

Example 15 Water-in-oil type emollient cream (1) Liquid paraffin 30.00 (% by weight) (2) Microcrystalline wax 2.00 (3) Vaseline 5.00 (4) Diglyceryl dioleic acid Ester 5.00 (5) Sodium L-glutamate 1.60 (6) L-Serine 0.40 (7) Propylene glycol 3.00 (8) Hyaluronic acid production promoter 8 0.05 (9) Methyl paraoxybenzoate 0.10 (10) Purified water 52.75 (11) Perfume 0.10 Manufacturing method: (5) and (6) were dissolved in a part of (10) to 50 ° C. and preheated to 50 ° C. ( Add slowly to 4) with stirring. This was mixed in advance and uniformly dispersed in (1) to (3) which was heated and dissolved at 70 ° C, and then (7) to (9) were dissolved in the rest of (10) and heated to 70 ° C. Add with stirring and emulsify with homomixer. After cooling, (1
Add 1) and mix.

[Example 16] Make-up base cream (1) Stearic acid 12.00 (% by weight) (2) Cetanol 2.00 (3) Glyceryl tri-2-ethylhexanoate 2.50 (4) Self-emulsification Type Glyceryl monostearic acid 2.00 Ester (5) Propylene glycol 10.00 (6) Potassium hydroxide 0.30 (7) Hyaluronic acid production promoter 5 0.05 (8) Methyl paraoxybenzoate 0.10 (9 ) Purified water 69.45 (10) Titanium oxide 1.00 (11) Red iron oxide 0.40 (12) Yellow iron oxide 0.10 (13) Perfume 0.10 Production method: Oil phase components of (1) to (4) Are mixed and melted to 75 ° C. On the other hand, the aqueous phase components (5) to (9) are mixed, heated and dissolved, and the pigment components (10) to (12) are added thereto, and the mixture is uniformly dispersed with a homomixer to 75 ° C. Next, the oil phase component is added to the aqueous phase component, and the mixture is uniformly emulsified with a homomixer. After cooling, (13) is added and mixed at 40 ° C.

Example 17 Emulsion foundation (1) Stearic acid 2.00 (wt%) (2) Squalane 5.00 (3) Octyldodecyl myristate 5.00 (4) Cetanol 1.00 (5) Decaglyceryl monoisopalmitic acid ester 9.00 (6) 1,3-butyleneglycol 6.00 (7) Potassium hydroxide 0.08 (8) Methyl paraoxybenzoate 0.10 (9) Purified water 53.42 (10) Titanium oxide 9.00 (11) Talc 7.40 (12) Red iron oxide 0.50 (13) Yellow iron oxide 1.10 (14) Black iron oxide 0.10 (15) Perfume 0.15 (16) Hyaluronic acid production promoter 1 0.15 Production method: Mix and dissolve the oil phase components (1) to (5) to 75 ° C. On the other hand, the water phase components (6) to (9) are mixed, heated and dissolved, and the pigment components (10) to (14) are added thereto, and the mixture is uniformly dispersed with a homomixer to 75 ° C. Next, the oil phase component is added to the aqueous phase component, and the mixture is uniformly emulsified with a homomixer. After cooling, (15) and (16) are added and mixed at 40 ° C.

Example 18 Hand Cream (1) Cetanol 4.00 (wt%) (2) Vaseline 2.00 (3) Liquid Paraffin 10.00 (4) Glyceryl Monostearate 1.50 (5) Polyoxyethylene (60 E.O.) glyceryl 2.50 isostearic acid ester (6) tocopherol acetate 0.25 (7) glycerin 20.00 (8) hyaluronic acid production promoter 6 0.02 (9) methyl paraoxybenzoate 0.10 (10) Purified water 59.58 (11) Hyaluronic acid production promoter 2 0.05 Manufacturing method: Mix and dissolve the oil phase components (1) to (6) to 75 ° C. On the other hand, the water phase components (7) to (10) are mixed and dissolved by heating to 7
Set to 5 ° C. Then, the oil phase component was added to the aqueous phase component to uniformly emulsify with a homomixer, and then cooled to 4
Add (11) at 0 ° C. and mix.

In Examples 9 to 14 among the above Examples of the present invention, the protective effect against the formation of wrinkles on the skin by ultraviolet rays was evaluated. In that case, in each example, hyaluronic acid production promoters 1 and 2 were impregnated with a 50% by volume aqueous ethanol solution and hyaluronic acid production promoter 3 was impregnated with a 50% by volume aqueous ethanol solution. Production promoter 4 was added to liposomes prepared in the same manner without the addition of dried and concentrated dry matter of yarrow flowers, Hyaluronic acid production promoter 5 was added to a 30% by volume aqueous solution of 1,3-butylene glycol, and hyaluronic acid production was promoted. Comparative Examples 1 to 6 prepared by substituting 25% by volume of 1,2-pentanediol for Agent 6 and purified water for Hyaluronic acid production promoter 7 were also evaluated at the same time.

Protective effect against wrinkle formation by ultraviolet rays
Is performed for each group with 5 hairless mice as one group
Example and comparative example were applied to the back once a day, and 1 J /
cm ²/ Weekly long wavelength ultraviolet (UVA) irradiation for 50 weeks
And observe wrinkle formation in hairless mouse skin
Then, it was scored and evaluated according to the following criteria. This
At this time, a group to which only purified water was applied was used as a control. The result is each
Calculate the average value of the group and display it in relation to the number of UVA irradiation days.
Shown in 3.

[Status of Wrinkle Formation on Skin] No wrinkle formation 0 points 1 point to slightly recognize the formation of minute wrinkles Two points that clearly recognize the formation of slight wrinkles 3 points that allow the formation of moderate wrinkles 4 points to recognize the formation of deep wrinkles

[0046]

[Table 3]

As is clear from Table 3, in the control group, the wrinkles formed on the skin reached a moderate depth when the number of UVA irradiation days exceeded 40 weeks, and deep wrinkles appeared after 50 weeks. Formation was observed. On the other hand, in each of the application groups of the present invention, the formation of fine or slight wrinkles was observed after 50 weeks in all cases, and the formation of wrinkles was significantly suppressed. On the other hand, in the Comparative Example-applied group, a slight reduction in the degree of wrinkles formed in the Comparative Example 2-applied group containing tocopherol acetate was observed, but no significant wrinkle formation inhibition or reduction was observed.

Subsequently, the above-mentioned Examples 9 to 14 and Comparative Examples 1 to 6 were evaluated for their anti-inflammatory action and wound healing promoting action. Five mice artificially inflamed or wounded on the back skin were made into one group, and 0.5 g each of the Example and Comparative Example was applied to the inflamed site or wound site twice a day for 7 days in each group. . The condition of each part was observed on the 7th day, and "effective", "somewhat effective", "ineffective" for the anti-inflammatory effect, "complete healing", "almost healing", "incomplete healing" for the wound healing promoting effect. The results are shown in Table 4 in terms of the number of mice each evaluated.

[0049]

[Table 4]

As is clear from Table 4, no mice evaluated as ineffective were found in any of the groups applied with the examples of the present invention with respect to the anti-inflammatory effect, and the effective anti-inflammatory effect was effective in two or more mice. Was recognized. Regarding the effect of promoting wound healing, none of the mice incompletely healing wounds was observed in the application group of the present invention, and complete healing was observed in two or more mice. On the other hand, in the comparative example-applied group, no effective anti-inflammatory effect was observed, except for the comparative example 2-applied group, which showed a slightly effective anti-inflammatory effect in one case. Wound healing was incomplete in all the applied groups.

Next, Examples 9 to 18 of the present invention were subjected to a practical use test for 6 months. At this time, in Examples 15 to 18, hyaluronic acid production promoter 1
And 2 in the same manner as above in 50% by volume aqueous ethanol solution, and 30% by volume of hyaluronic acid production promoters 5 and 6
Comparative Examples 7 to 10 were prepared by substituting purified water for the hyaluronic acid production promoter 8 into 3-butylene glycol and 25% by volume of 1,2-pentanediol. In the practical use test, as a panel, 20 females in their 40s to 60s who exhibited remarkable skin aging symptoms such as wrinkles and decreased skin elasticity were used as 20 groups per group, and each Example and Comparative Example were blinded. I used it twice a day. The skin condition was observed before and after the start of the use test, and the improvement status of wrinkles and skin elasticity was evaluated in three grades of "improved", "slightly improved", and "no change". The degree of wrinkles was evaluated by photographing and replica sampling, and the elasticity of the skin was evaluated by measuring with a cute meter. The results are shown in Table 5 by the number of panelists who obtained each evaluation.

[0052]

[Table 5]

As is clear from Table 5, in all of the groups used in the examples of the present invention, the symptoms were improved in all the panelists in terms of wrinkles and skin elasticity. In particular, Example 9-
In the group used in Example 14, the wrinkles were 40% or more, and the skin elasticity was 50% or more. On the other hand, in any of the groups used in Comparative Examples, no panelists showed a clear improvement in both wrinkles and skin elasticity, and wrinkles were observed in 80% or more and skin elasticity in 75% or more. No change was seen in the condition.

In addition, in Examples 1 to 8 of the present invention, when stored at 10 ° C. or lower, the hyaluronic acid production promoting action was maintained almost unchanged for 6 months. In addition, regarding Examples 9 to 18 of the present invention,
When stored at 25 ° C for 6 months, no state change was observed. Furthermore, in the above-mentioned actual use test, in the use group of Examples of the present invention, no panelist recognized skin irritation reaction or skin sensitization reaction, and irritation sensation such as pain and warmth, tingling sensation, tingling sensation during use. Or, there was no panelist who complained of discomfort.

[0055]

INDUSTRIAL APPLICABILITY As described in detail above, according to the present invention, it has an excellent hyaluronic acid production-promoting action on fibroblasts, and also has good stability and safety, and is suitable for external use. It is possible to obtain an agent, and by applying it, prevention of skin aging symptoms,
It was possible to provide a skin external preparation useful for improvement, promotion of wound healing, and treatment of diseases associated with abnormal decomposition of hyaluronic acid.

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Claims (2)

(57) [Claims] 1. A cell medical yarrow (Achillea mille
folium L.) flower extract, one or more kinds thereof being contained, hyaluronic acid production promoter. 2. The hyaluronic acid production promoter according to claim 1, wherein the extract is an extract with a polar solvent.