JP2007084508A - New vascular endothelial growth factor expression inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new vascular endothelial growth factor expression inhibitor. <P>SOLUTION: This anti-aging agent, angiogenesis inhibitor, or vascular endothelial growth factor expression inhibitor comprises one or two galenicals selected from the group consisting of Mukurossi Peel Extract and Hazelnut Extract. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to an anti-aging agent, particularly an anti-aging agent exhibiting an anti-photoaging effect, an angiogenesis inhibitor, or a VEGF expression inhibitor.

  Angiogenesis refers to a phenomenon in which blood vessels are newly formed. In blood vessels, the basement membrane of blood vessels is degraded by the action of proteolytic enzymes in tissues or organs. It is newly formed by forming. In addition to normal reactions such as the wound healing process, angiogenesis is the growth and metastasis of cancer, diabetic retinopathy, neovascular glaucoma, inflammatory skin diseases, psoriasis, rheumatoid arthritis, osteoarthritis, age-related macular It is also known to be involved in the pathogenesis of various diseases such as degeneration, chronic bronchitis, atherosclerosis, myocardial infarction, or worsening of the disease state.

  Among the angiogenic factors, vascular endothelial growth factor “VEGF” is used for vascular endothelial cell proliferation induction and survival maintenance, vascular permeability enhancement, blood pressure regulation, platelet migration, macrophage chemotaxis, etc. It functions not only in newborns, but also in vascular, blood and coagulation systems. A compound that inhibits the expression or activity of VEGF in vascular endothelial cells is used as an angiogenesis inhibitor to cure or prevent various diseases including the above cancer, diabetic retinopathy and various arthritis, or to prevent or improve skin aging. Expected to be a drug.

  Recently, it has been reported that endothelial cells in the vascular system of skin are also involved in skin aging (International Publication WO2003 / 084302).

  The skin vasculature is essential to maintain the structure and function of normal skin. Beyond that, the vasculature of the skin plays a major role in controlling hair growth, sedating skin damage due to ultraviolet light, aging-induced skin aging, skin response to irritation and inflammation, and tissue repair. Although blood vessels work regularly in normal adult skin, they react rapidly with different stimuli and react with vasodilation and angiogenesis that forms new capillaries from existing blood vessels. These changes depend on the balance between both pro-angiogenic molecules (angiogenesis-promoting factors) and anti-angiogenic molecules (anti-angiogenic factors). In normal skin, it has been found that the endogenous angiogenesis inhibitory factor works more preferentially than the angiogenesis promoting factor.

  VEGF, also known as a vascular permeability factor, recent studies have suggested that it is a major pro-angiogenic factor in human skin. In normal skin, VEGF is secreted in small amounts by keratinocytes and maintains the upper reticulated blood vessels by binding to specific receptors on the dermal microvascular endothelial cells, thereby ensuring the viability of the endothelial cells is doing. VEGF in the thickened epidermis during inflammation or wound healing is very highly expressed and therefore leads to increased blood vessels and nutrient supply in the dermis due to the epidermis without blood vessels.

  In vivo studies using transgenic models that overexpress VEGF and angiogenesis-inhibiting factors in the skin have shown that the regulation of the levels of these angiogenesis-promoting factors and angiogenesis-inhibiting factors is related to the extent of UV damage and skin wrinkles. It has been shown to have a significant effect on irritating skin reactions and repair of skin damage (WO 2003/084302).

  When mice were exposed to ultraviolet light for a long period of time, remarkable wrinkles were formed, and surprisingly, remarkable growth of subcutaneous blood vessels was observed with enlargement of blood vessels and increased branching. It was also found that the expression of vascular endothelial growth factor is enhanced when mice are irradiated with ultraviolet rays for a long period of time. From this, it is clear that the formation of wrinkles due to skin damage such as ultraviolet irradiation is involved in the formation of vascular endothelial cells, in other words, the inhibition of the formation of vascular endothelial cells, and the vascular endothelial cells It is clear that wrinkle formation can be suppressed by inducing cell death.

International Publication No. WO2003 / 084302

  An object of the present invention is to provide a novel anti-aging agent, angiogenesis inhibitor or VEGF expression inhibitor.

  As a result of intensive studies, the present inventor has found that certain crude drugs, ie, Mukurossi Peel Extract and Hazelnut Extract, inhibit VEGF expression.

  Accordingly, the present invention provides an anti-aging agent containing one or two kinds of drugs selected from the group consisting of mukuroji extract and hazelnut extract. Such an anti-aging agent is extremely effective in preventing or suppressing wrinkle formation, particularly wrinkle formation due to photoaging.

  The invention further relates to a method for inhibiting aging, comprising applying the anti-aging agent to the skin.

  In another aspect, the present invention provides an angiogenesis inhibitor containing one or two drugs selected from the group consisting of mukuroji extract and hazelnut extract. The present invention further provides a VEGF expression inhibitor containing one or two drugs selected from the group consisting of mukuroji extract and hazelnut extract.

  Mukuroji extract and hazelnut extract are effective in suppressing skin aging and treating / preventing diseases caused by angiogenesis such as cancer.

  As described in detail in the Examples and Experiments 1 below, various crude drug screens that inhibit the expression of VEGF can be applied to the HaCat cell line into which a DNA construct in which a luciferase is bound as a reporter gene is introduced downstream of the VEGF promoter. The drug was allowed to act, the luciferase activity was measured, the inhibition of the luciferase activity was regarded as VEGF expression inhibition, and the drug having the VEGF expression inhibition activity was selected as an effective drug. Moreover, the presence or absence of the actual VEGF expression inhibitory effect in a normal cell was confirmed about the medicine selected in this way.

  As a result, it was found that mugwort extract and hazelnut extract significantly inhibit VEGF expression.

Mukuroji extract: An extract extracted from the skin of mukuroji (Sapondus mukurossi Gaertner (Sapindaceae)). It is a natural ingredient often used in toothpaste, shampoo and soap.
Hazelnut extract: An extract extracted from the seeds of hazelnut (Guevina avellana Mol (Proteaceae). From this fruit, edible oil used for cooking is collected, but at the same time, this oil serves to prevent skin dryness, soap, Used for packs and massage oils.

  The above extract can be obtained by a conventional method. For example, a plant that is the origin of each extract can be obtained by immersing or heating under reflux with an extraction solvent, followed by filtration and concentration. As the extraction solvent, any solvent that is usually used for extraction can be used. For example, water, methanol, ethanol, propylene glycol, 1,3-butylene glycol, glycerin and other alcohols, hydrous alcohols, chloroform , Organic solvents such as dichloroethane, carbon tetrachloride, acetone, ethyl acetate, hexane and the like can be used alone or in combination. The extract obtained by extraction with the above solvent is used as it is, or the concentrated extract is adsorbed by an adsorption method, for example, by removing impurities using an ion exchange resin, or by a column of a porous polymer (for example, Amberlite XAD-2). Then, it can be used after elution with methanol or ethanol. In addition, a partition method, for example, an extract extracted with water / ethyl acetate may be used.

  The herbal medicine according to the present invention is extremely effective in preventing and suppressing aging caused by neovascularization, growth and proliferation of vascular endothelial cells. Aging caused by neovascularization, growth and proliferation of vascular endothelial cells means photoaging due to skin injury or exposure to ultraviolet rays. The herbal medicine according to the present invention is particularly effective in preventing and suppressing photoaging.

  Photoaging refers to changes in the appearance and function of the skin that are generally recognized as a result of repeated exposure to sunlight. Ultraviolet rays (UV), which is a component of sunlight, particularly intermediate UV (wavelength 290-320 nm, called UVB) mainly cause photoaging. The amount of UVB exposure necessary to cause photoaging is currently unknown. However, repeated exposure to UVB at levels that cause erythema and sunburn usually leads to photoaging. Clinically, photoaging is rough skin, wrinkle formation, spot coloring, soil coloration, sagging formation, onset of telangiectasia, development of mole, onset of purpura, vulnerable, atrophy, fibrosis It can be specified as the occurrence of a pigment removal region, the development of a pre-malignant tumor, a malignant tumor, and the like. Photoaging usually occurs in skin that is habitually exposed to sunlight, such as the face, ears, head, neck, and hands.

  Further, the angiogenesis inhibitor or VEGF expression inhibitor of the present invention is used for promoting wound healing, vascular endothelial cell neoplasia, growth, cancer proliferation and metastasis involving proliferation, diabetic retinopathy, angiogenesis glaucoma, inflammatory It can be used as a pharmaceutical or cosmetic effective for the treatment and prevention of diseases such as skin diseases, psoriasis, rheumatoid arthritis, osteoarthritis, age-related macular degeneration, chronic bronchitis, atherosclerosis and myocardial infarction.

  The compounding amount of the crude drug for inhibiting angiogenesis in the anti-aging agent, angiogenesis inhibitor or VEGF expression inhibitor of the present invention is 0.0001 to 20.0% by mass, preferably 0.0001 to 10.0% by mass as a dry product in the total amount of the agent. It is.

  In addition to the above essential components, the anti-aging agent, angiogenesis inhibitor or VEGF expression inhibitor of the present invention, in addition to the above essential components, components that are usually used in skin external preparations such as cosmetics and pharmaceuticals, such as whitening agents, Used in moisturizers, antioxidants, oily ingredients, UV absorbers, surfactants, thickeners, alcohols, powder ingredients, colorants, aqueous ingredients, water, various skin nutrients, etc. Ingredients such as excipients, moisture-proofing agents, preservatives, reinforcing agents, thickeners, emulsifiers, antioxidants, sweeteners, acidulants, seasonings, colorants, flavors, and the like are appropriately blended as necessary. can do.

  Others, disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, sequestering agents such as gluconic acid, caffeine, tannin, verapamil, tranexamic acid and its derivatives, licorice extract, grabrizine , Hot water extract of karin fruit, various herbal medicines, drugs such as tocopherol acetate, glycyrrhizic acid and its derivatives or salts thereof, whitening agents such as vitamin C, magnesium ascorbate phosphate, glucoside ascorbate, arbutin, kojic acid, Sugars such as glucose, fructose, mannose, sucrose, and trehalose, vitamin A such as retinoic acid, retinol, retinol acetate, and retinol palmitate can also be appropriately blended.

  The anti-aging agent of the present invention may be any one as long as it is used for conventional skin external preparations such as ointments, creams, emulsions, lotions, packs, bath preparations and the like, and the dosage form is not particularly limited.

The anti-aging agent of the present invention can be used in a cosmetic method for preventing and improving aging by applying to the skin. The usage and dose of the anti-aging agent of the present invention in such a cosmetic method are not particularly limited, and are appropriately determined depending on the dosage form and the state of wrinkles on the skin to be treated. Typically, several times a day, For example, an appropriate amount, for example, 0.1 ml to 1 ml per 1 cm ² , can be directly rubbed into the skin, or the appropriate amount can be soaked in gauze and applied to the skin.

  The angiogenesis inhibitor or VEGF expression inhibitor of the present invention can be appropriately determined in dosage, usage, and dosage form according to the purpose of use. For example, the administration form of the angiogenesis inhibitor or VEGF expression inhibitor of the present invention may be oral, parenteral, external use and the like. Examples of the dosage form include oral preparations such as tablets, powders, capsules, granules, extracts, and syrups, or parenteral preparations such as injections, drops, and suppositories, ointments, creams, emulsions, and lotions. And external preparations such as packs and bath preparations.

  Next, the present invention will be described in more detail with reference to examples. In addition, this invention is not limited by this. A compounding quantity is the mass%.

Experiment 1.
Screening for crude drugs having VEGF expression inhibitor activity A cell line in which a DNA construct in which a luciferase-encoding gene was bound as a reporter gene downstream of the VEGF promoter was stably introduced into HaCaT cells was used. Suspend the above cell line in DMEM (Invitrogen) (containing 10% FBS (ICN) and 400 μg / ml G418 (Promega)) medium to make 4 × 10 ⁴ cells per well in a 24-well plate. And 5% CO ₂ at 37 ° C. After about 24 hours, various plant extract dried products as candidate drugs dissolved in DMSO (Wako Pure Chemical Industries, Ltd.) were used as final concentrations of 10 ⁻⁴ , 10 ⁻³ , 10 ⁻² % with respect to the culture solution. In addition, the cells were cultured for 24 hours. After removing the culture supernatant, the cells were washed with PBS, and luciferase activity was measured using Luciferase Assay System (Promega).
In order to measure the luciferase activity of cells, the amount of DNA per well was measured using Hoechst 33342 (Sigma) at a final concentration of 10 μg / ml, which was used as an indicator of the number of cells per well. Luciferase activity was determined.
As a result, it was shown that among the various plant extracts that were tested, mukuroji extract and hazelnut extract (Maruzen Pharmaceutical) inhibited VEGF expression in a concentration-dependent manner. The result is shown in FIG. In the control, only DMSO was allowed to act instead of the candidate drug.

Experiment 2.
Quantitative analysis of VEGF protein in normal cells With regard to the herbal medicine mugwort extract and hazelnut extract in which the suppressive effect of promoter activity was confirmed by the luciferase assay in Experiment 1, the presence or absence of an actual VEGF protein expression inhibitory effect in normal cells was confirmed.
Normal human keratinocytes (Kurabo) were suspended in KGM medium (Kurabo), seeded in a 24-well plate at 4 × 10 ⁴ cells per well, and cultured at 37 ° C. with 5% CO ₂ . About 24 hours later, the dried linden extract was dissolved in DMSO (Wako Pure Chemical Industries, Ltd.), and 10 ⁻³ , 3.3 × 10 ⁻³ , and 10 ⁻² % were added as final concentrations with respect to the culture solution. Cultured for 24 hours. The VEGF protein in the culture supernatant was measured using ELISA (R & D Systems).
As a result, it was confirmed that the mugwort extract and hazelnut extract inhibit the expression of VEGF in a concentration-dependent manner. The result is shown in FIG. In the control, only DMSO was allowed to act instead of the candidate drug.

(Example 1) Cream (combination component) (mass%)
(1) Stearic acid 5.0
(2) Stearyl alcohol 4.0
(3) Isopropyl myristate 18.0
(4) Glycerol monostearate 3.0
(5) Propylene glycol 10.0
(6) Mukuroji extract 0.01
(7) Caustic potash 0.2
(8) Sodium bisulfite 0.01
(9) Preservative Appropriate amount (10) Fragrance Appropriate amount (11) Ion-exchanged water Residue (Preparation) Add (5) to (7) to (11), dissolve, heat and keep at 70 ° C (aqueous phase ). On the other hand, (1) to (4) and (8) to (10) are mixed, heated and melted, and kept at 70 ° C. (oil phase). The oil phase is gradually added to the aqueous phase, and after the addition is completed, the temperature is maintained for a while to cause the reaction. Thereafter, the mixture is uniformly emulsified with a homomixer and cooled to 30 ° C. while stirring well.

(Example 2) Cream (combination component) (mass%)
(1) Stearic acid 2.0
(2) Stearyl alcohol 7.0
(3) Hydrogenated lanolin 2.0
(4) Squalane 5.0
(5) 2-Octyldodecyl alcohol 6.0
(6) Polyoxyethylene (25 mol) cetyl alcohol ether 3.0
(7) Glycerin monostearate ester 2.0
(8) Propylene glycol 5.0
(9) Hazelnut extract 0.05
(10) Sodium bisulfite 0.03
(11) Ethylparaben 0.3
(12) Fragrance appropriate amount (13) Ion-exchanged water Residue (Preparation method) Add (8) to (13) and heat to keep at 70 ° C. (aqueous phase). On the other hand, (1) to (7) and (9) to (12) are mixed, heated and melted and kept at 70 ° C. (oil phase). The oil phase is added to the aqueous phase, pre-emulsified, and uniformly emulsified with a homomixer, and then cooled to 30 ° C. while stirring well.

(Example 3) Cream (combination component) (mass%)
(1) Solid paraffin 5.0
(2) Beeswax 10.0
(3) Vaseline 15.0
(4) Liquid paraffin 41.0
(5) Glycerin monostearate ester 2.0
(6) Polyoxyethylene (20 mol) sorbitan monolaurate 2.0
(7) Soap powder 0.1
(8) Borax 0.2
(9) Mukuroji extract 0.05
(10) Hazelnut extract 0.05
(11) Sodium bisulfite 0.03
(12) Ethylparaben 0.3
(13) Perfume appropriate amount (14) Ion-exchanged water Residue (Production method) Add (7) and (8) to (14) and heat to keep at 70 ° C. (aqueous phase). On the other hand, (1) to (6) and (9) to (14) are mixed, heated and melted and kept at 70 ° C. (oil phase). The reaction is carried out by gradually adding the oil phase to the aqueous phase while stirring. After completion of the reaction, the mixture is uniformly emulsified with a homomixer, and cooled to 30 ° C. while thoroughly stirring after emulsification.

(Example 4) Emulsion (combined component) (mass%)
(1) Stearic acid 2.5
(2) Cetyl alcohol 1.5
(3) Vaseline 5.0
(4) Liquid paraffin 10.0
(5) Polyoxyethylene (10 mol) monooleate 2.0
(6) Polyethylene glycol 1500 3.0
(7) Triethanolamine 1.0
(8) Carboxyvinyl polymer 0.05
("Carbopol 941", BFGoodrich)
(9) Mukuroji extract 0.01
(10) Sodium bisulfite 0.01
(11) Ethylparaben 0.3
(12) Perfume appropriate amount (13) Ion exchange water Residue (Preparation method) Dissolve (8) in a small amount of (13) (phase A). On the other hand, (6) and (7) are added to the remaining (13), dissolved by heating and kept at 70 ° C. (aqueous phase). (1) to (5) and (9) to (12) are mixed, heated and melted and kept at 70 ° C. (oil phase). Add oil phase to water phase, pre-emulsify, add phase A, uniformly emulsify with homomixer, and cool to 30 ° C. while stirring well after emulsification.

(Example 5) Emulsion (combined component) (mass%)
(1) Microcrystalline wax 1.0
(2) Beeswax 2.0
(3) Lanolin 20.0
(4) Liquid paraffin 10.0
(5) Squalane 5.0
(6) Sorbitan sesquioleate ester 4.0
(7) Polyoxyethylene (20 mol) sorbitan monooleate 1.0
(8) Propylene glycol 7.0
(9) Hazelnut extract 1.0
(10) Sodium bisulfite 0.01
(11) Ethylparaben 0.3
(12) Fragrance appropriate amount (13) Ion-exchanged water Residue (Preparation method) Add (8) to (13) and heat to keep at 70 ° C. (aqueous phase). On the other hand, (1) to (7) and (9) to (12) are mixed, heated and melted and kept at 70 ° C. (oil phase). The water phase is gradually added to the oil phase while stirring, and the mixture is uniformly emulsified with a homomixer. After emulsification, cool to 30 ° C. with good mixing.

(Example 6) Jelly (combined component) (mass%)
(1) 95% ethyl alcohol 10.0
(2) Dipropylene glycol 15.0
(3) Polyoxyethylene (50 mol) oleyl alcohol ether 2.0
(4) Carboxyvinyl polymer 1.0
(Carbopol 940, BFGoodrich)
(5) Caustic soda 0.15
(6) L-arginine 0.1
(7) Mukuroji extract 7.0
(8) Sodium 2-hydroxy-4-methoxybenzophenone sulfonate 0.05
(9) Ethylenediaminetetraacetate, 3Na, 2water 0.05
(10) Methylparaben 0.2
(11) Perfume appropriate amount (12) ion-exchanged water (4) is uniformly dissolved in the remainder (production method) (12) (aqueous phase). On the other hand, (7) and (3) are dissolved in (1) and added to the aqueous phase. Next, after adding (2) and (8) to (11), the mixture is neutralized and thickened with (5) and (6).

(Example 7) Essence (combination component) (mass%)
(Phase A)
Ethyl alcohol (95%) 10.0
Polyoxyethylene (20 mol) octyldodecanol 1.0
Pantotenyl ethyl ether 0.1
Hazelnut extract 1.5
Methylparaben 0.15
(Phase B)
Potassium hydroxide 0.1
(Phase C)
Glycerin 5.0
Dipropylene glycol 10.0
Sodium bisulfite 0.03
Carboxyvinyl polymer 0.2
(Carbopol 940, BFGoodrich)
Purified water residue (Manufacturing method) A phase and C phase are uniformly dissolved, and A phase is added to C phase to solubilize. The phase B is then added and then filled into a container.

(Example 8) Pack (combined component) (mass%)
(Phase A)
Dipropylene glycol 5.0
Polyoxyethylene (60 mol) hydrogenated castor oil 5.0
(Phase B)
Mukuroji extract 0.01
Olive oil 5.0
Tocopherol acetate 0.2
Ethylparaben 0.2
Fragrance 0.2
(Phase C)
Sodium bisulfite 0.03
Polyvinyl alcohol (saponification degree 90, polymerization degree 2,000) 13.0
Ethanol 7.0
Purified water residue (Manufacturing method) A phase, B phase and C phase are uniformly dissolved, and B phase is added to A phase to solubilize. This is then added to Phase C and then filled into a container.

(Example 9) Solid foundation (combined component) (mass%)
(1) Talc 43.1
(2) Kaolin 15.0
(3) Sericite 10.0
(4) Zinc flower 7.0
(5) Titanium dioxide 3.8
(6) Yellow iron oxide 2.9
(7) Black iron oxide 0.2
(8) Squalane 8.0
(9) Isostearic acid 4.0
(10) POE sorbitan monooleate 3.0
(11) Isocetyl octanoate 2.0
(12) Hazelnut extract 1.0
(13) Preservative Appropriate amount (14) Fragrance Appropriate amount (Manufacturing method) The powder components of (1) to (7) are sufficiently mixed with a blender, to which (8) to (11) oily components, (12), (13), (14) is added and kneaded well, then filled into a container and molded.

(Example 10) Emulsion type foundation (cream type)
(Mixed component) (mass%)
(Powder part)
Titanium dioxide 10.3
Sericite 5.4
Kaolin 3.0
Yellow iron oxide 0.8
Bengala 0.3
Black iron oxide 0.2
(Oil phase)
Decamethylcyclopentasiloxane 11.5
Liquid paraffin 4.5
Polyoxyethylene-modified dimethylpolysiloxane 4.0
(Water phase)
Purified water 51.0
1,3-butylene glycol 4.5
Mukuroji Extract 1.5
Sorbitan sesquioleate 3.0
Preservative Appropriate amount Fragrance Appropriate amount (Manufacturing method) After heating and stirring the aqueous phase, add the sufficiently mixed and pulverized powder part and homogenize. Furthermore, after adding the heat-mixed oil phase and carrying out a homomixer process, a fragrance | flavor is added, stirring, and it cools to room temperature.

(Example 11) Cream (combined component) (mass%)
(1) Stearic acid 5.0
(2) Stearyl alcohol 4.0
(3) Isopropyl myristate 18.0
(4) Glycerol monostearate 3.0
(5) Propylene glycol 10.0
(6) Hazelnut extract 0.01
(7) Caustic potash 0.2
(8) Sodium bisulfite 0.01
(9) Preservative Appropriate amount (10) Fragrance Appropriate amount (11) Ion-exchanged water Residue (Preparation) Add (5) to (7) to (11), dissolve, heat and keep at 70 ° C (aqueous phase ). On the other hand, (1) to (4) and (8) to (10) are mixed, heated and melted, and kept at 70 ° C. (oil phase). The oil phase is gradually added to the aqueous phase, and after the addition is completed, the temperature is maintained for a while to cause the reaction. Thereafter, the mixture is uniformly emulsified with a homomixer and cooled to 30 ° C. while stirring well.

(Example 12) Cream (combined component) (mass%)
(1) Stearic acid 2.0
(2) Stearyl alcohol 7.0
(3) Hydrogenated lanolin 2.0
(4) Squalane 5.0
(5) 2-Octyldodecyl alcohol 6.0
(6) Polyoxyethylene (25 mol) cetyl alcohol ether 3.0
(7) Glycerin monostearate ester 2.0
(8) Propylene glycol 5.0
(9) Mukuroji extract 0.05
(10) Sodium bisulfite 0.03
(11) Ethylparaben 0.3
(12) Fragrance appropriate amount (13) Ion-exchanged water Residue (Preparation method) Add (8) to (13) and heat to keep at 70 ° C. (aqueous phase). On the other hand, (1) to (7) and (9) to (12) are mixed, heated and melted and kept at 70 ° C. (oil phase). The oil phase is added to the aqueous phase, pre-emulsified, and uniformly emulsified with a homomixer, and then cooled to 30 ° C. while stirring well.

(Example 13) Cream (combination component) (mass%)
(1) Solid paraffin 5.0
(2) Beeswax 10.0
(3) Vaseline 15.0
(4) Liquid paraffin 41.0
(5) Glycerin monostearate ester 2.0
(6) Polyoxyethylene (20 mol) sorbitan monolaurate 2.0
(7) Soap powder 0.1
(8) Borax 0.2
(9) Hazelnut extract 0.05
(10) Sodium bisulfite 0.03
(11) Ethylparaben 0.3
(12) Perfume appropriate amount (13) Ion-exchanged water The remaining (production method) (7), (8) are added to (13) and heated to 70 ° C. (water phase). On the other hand, (1) to (6) and (9) to (13) are mixed, heated and melted, and kept at 70 ° C. (oil phase). The reaction is carried out by gradually adding the oil phase to the aqueous phase while stirring. After completion of the reaction, the mixture is uniformly emulsified with a homomixer, and cooled to 30 ° C. while thoroughly stirring after emulsification.

(Example 14) Emulsion (combined component) (mass%)
(1) Stearic acid 2.5
(2) Cetyl alcohol 1.5
(3) Vaseline 5.0
(4) Liquid paraffin 10.0
(5) Polyoxyethylene (10 mol) monooleate 2.0
(6) Polyethylene glycol 1500 3.0
(7) Triethanolamine 1.0
(8) Carboxyvinyl polymer 0.05
("Carbopol 941", BFGoodrich)
(9) Mukuroji extract 0.01
(10) Sodium bisulfite 0.01
(11) Ethylparaben 0.3
(12) Perfume appropriate amount (13) Ion exchange water Residue (Preparation method) Dissolve (8) in a small amount of (13) (phase A). On the other hand, (6) and (7) are added to the remaining (13), dissolved by heating and kept at 70 ° C. (aqueous phase). (1) to (5) and (9) to (12) are mixed, heated and melted and kept at 70 ° C. (oil phase). Add oil phase to water phase, pre-emulsify, add phase A, uniformly emulsify with homomixer, and cool to 30 ° C. while stirring well after emulsification.

(Example 15) Emulsion (combined component) (mass%)
(1) Microcrystalline wax 1.0
(2) Beeswax 2.0
(3) Lanolin 20.0
(4) Liquid paraffin 10.0
(5) Squalane 5.0
(6) Sorbitan sesquioleate ester 4.0
(7) Polyoxyethylene (20 mol) sorbitan monooleate 1.0
(8) Propylene glycol 7.0
(9) Hazelnut extract 1.0
(10) Sodium bisulfite 0.01
(11) Ethylparaben 0.3
(12) Fragrance appropriate amount (13) Ion-exchanged water Residue (Preparation method) Add (8) to (13) and heat to keep at 70 ° C. (aqueous phase). On the other hand, (1) to (7) and (9) to (12) are mixed, heated and melted and kept at 70 ° C. (oil phase). The water phase is gradually added to the oil phase while stirring, and the mixture is uniformly emulsified with a homomixer. After emulsification, cool to 30 ° C. with good mixing.

(Example 16) Jelly (combined component) (mass%)
(1) 95% ethyl alcohol 10.0
(2) Dipropylene glycol 15.0
(3) Polyoxyethylene (50 mol) oleyl alcohol ether 2.0
(4) Carboxyvinyl polymer 1.0
(Carbopol 940, BFGoodrich)
(5) Caustic soda 0.15
(6) L-arginine 0.1
(7) Mukuroji extract 7.0
(8) Sodium 2-hydroxy-4-methoxybenzophenone sulfonate 0.05
(9) Ethylenediaminetetraacetate, 3Na, 2water 0.05
(10) Methylparaben 0.2
(11) Perfume appropriate amount (12) ion-exchanged water (4) is uniformly dissolved in the remainder (production method) (12) (aqueous phase). On the other hand, (7) and (3) are dissolved in (1) and added to the aqueous phase. Next, after adding (2) and (8) to (11), the mixture is neutralized and thickened with (5) and (6).

(Example 17) Essence (composition component) (mass%)
(Phase A)
Ethyl alcohol (95%) 10.0
Polyoxyethylene (20 mol) octyldodecanol 1.0
Pantotenyl ethyl ether 0.1
Hazelnut extract 1.5
Methylparaben 0.15
(Phase B)
Potassium hydroxide 0.1
(Phase C)
Glycerin 5.0
Dipropylene glycol 10.0
Sodium bisulfite 0.03
Carboxyvinyl polymer 0.2
(Carbopol 940, BFGoodrich)
Purified water residue (Manufacturing method) A phase and C phase are uniformly dissolved, and A phase is added to C phase to solubilize. The phase B is then added and then filled into a container.

(Example 18) Pack (combined component) (mass%)
(Phase A)
Dipropylene glycol 5.0
Polyoxyethylene (60 mol) hydrogenated castor oil 5.0
(Phase B)
Mukuroji extract 0.01
Olive oil 5.0
Tocopherol acetate 0.2
Ethylparaben 0.2
Fragrance 0.2
(Phase C)
Sodium bisulfite 0.03
Polyvinyl alcohol (saponification degree 90, polymerization degree 2,000) 13.0
Ethanol 7.0
Purified water residue (Manufacturing method) A phase, B phase and C phase are uniformly dissolved, and B phase is added to A phase to solubilize. This is then added to Phase C and then filled into a container.

(Example 19) Solid foundation (combined component) (mass%)
(1) Talc 43.1
(2) Kaolin 15.0
(3) Sericite 10.0
(4) Zinc flower 7.0
(5) Titanium dioxide 3.8
(6) Yellow iron oxide 2.9
(7) Black iron oxide 0.2
(8) Squalane 8.0
(9) Isostearic acid 4.0
(10) POE sorbitan monooleate 3.0
(11) Isocetyl octanoate 2.0
(12) Hazelnut extract 1.0
(13) Preservative Appropriate amount (14) Fragrance Appropriate amount (Manufacturing method) The powder components of (1) to (7) are sufficiently mixed with a blender, to which (8) to (11) oily components, (12), (13), (14) is added and kneaded well, then filled into a container and molded.

(Example 20) Emulsion type foundation (cream type)
(Mixed component) (mass%)
(Powder part)
Titanium dioxide 10.3
Sericite 5.4
Kaolin 3.0
Yellow iron oxide 0.8
Bengala 0.3
Black iron oxide 0.2
(Oil phase)
Decamethylcyclopentasiloxane 11.5
Liquid paraffin 4.5
Polyoxyethylene-modified dimethylpolysiloxane 4.0
(Water phase)
Purified water 51.0
1,3-butylene glycol 4.5
Mukuroji Extract 1.5
Sorbitan sesquioleate 3.0
Preservative Appropriate amount Fragrance Appropriate amount (Manufacturing method) After heating and stirring the aqueous phase, add the sufficiently mixed and pulverized powder part and homogenize. Furthermore, after adding the heat-mixed oil phase and carrying out a homomixer process, a fragrance | flavor is added, stirring, and it cools to room temperature.

(Example 21) Mukuroji extract for injection 100 mg
Maltosyl-β-cyclodextrin 726mg
Sodium hydroxide 33.3μg
Distilled water for injection Total volume 5.0ml
100 mg of Mukuroji extract was added to distilled water for injection in which 726 mg of maltosyl-β-cyclodextrin was dissolved. An aqueous solution of sodium hydroxide (33.3 μg) was added thereto to prepare a total amount of 5 ml, followed by filtration. This was filled in a vial and then freeze-dried to obtain an injection.

(Example 22) Tablet hazelnut extract 1g
Polyethylene glycol 6000 10g
Sodium lauryl sulfate 1.5g
Corn starch 3g
Lactose 25g
Magnesium stearate 0.5g
(Manufacturing method) The said component is weighed. Polyethylene glycol 6000 is heated to 70-80 ° C. and mixed with hazelnut extract, sodium lauryl sulfate, corn starch and lactose, and then cooled. The solidified mixture is granulated by a pulverizer to obtain granules. The granules are mixed with magnesium stearate and compressed into tablets with a weight of 250 mg.

(Example 23) Tablet Mukuroji Extract 3g
Lactose 55g
Potato starch 12g
Polyvinyl alcohol 1.5g
Magnesium stearate 1.5g
(Production method) The above ingredients are weighed. Mix evenly with mugwort extract, lactose and potato starch. An aqueous solution of polyvinyl alcohol is added to the mixture, and granules are prepared by wet granulation. The granules are dried, mixed with magnesium stearate, and compressed into tablets with a weight of 200 mg.

Example 24 Capsule Hazelnut Extract 1g
Lactose 25g
Corn starch 5g
Microcrystalline cellulose 9.5g
Magnesium stearate 0.5g
(Production method) The above ingredients are weighed. 4 ingredients other than magnesium stearate are mixed uniformly. Add the magnesium stearate and mix for a few more minutes. 200 mg of the mixture is filled into hard capsules to make capsules.

(Example 25) Powdered Mukuroji Extract 2g
Lactose 79g
Magnesium stearate 1g
(Manufacturing method) The said component is weighed. Mix all ingredients uniformly to form a powder.

Example 26 Suppository Hazelnut Extract 1g
Polyethylene glycol 1500 18g
Polyethylene glycol 4000 72g
(Manufacturing method) 1 g of rectal suppository is prepared by the melting method.

(Example 27) Injection hazelnut extract 0.1 g
Sodium chloride 0.9g
Sodium hydroxide appropriate amount of water for injection 100mL
(Manufacturing method) The said component is weighed. Dissolve the three components in water for injection, filter sterilize, dispense 5 mL each into a 10 mL ampoule, and seal to make an injection.

The result of the screening of the crude drug which has VEGF expression inhibitor activity by a luciferase assay is shown. The influence of VEGF protein expression with respect to the normal cell of a mugwort extract and a hazelnut extract is shown.

Claims (4)

  An anti-aging agent comprising one or two herbal medicines selected from the group consisting of Mukurossi Peel Extract and Hazelnut Extract.   An angiogenesis inhibitor comprising one or two kinds of herbal medicines selected from the group consisting of mukuroji extract and hazelnut extract.   An inhibitor of vascular endothelial growth factor (VEGF) expression, comprising one or two herbal medicines selected from the group consisting of mukuroji extract and hazelnut extract. A cosmetic method for inhibiting aging, comprising applying the anti-aging agent according to claim 1 to the skin.

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