JP2011126814A - Collagen production promoter, hyaluronic acid production promoter, and collagen production and hyaluronic acid production promoter - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a collagen production promotor, a hyaluronic acid production promotor, and a collagen production and hyaluronic acid production promotor which promote hyaluronic acid producibility in mammals such as a human and can be safely and simply used. <P>SOLUTION: The collagen production promotor, the hyaluronic acid production promotor, and the collagen production and hyaluronic acid production promotor comprise coronaric acid. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a collagen production promoter comprising coronalic acid, a hyaluronic acid production promoter, and a collagen production promotion and hyaluronic acid production promoter.

  The skin is composed of the stratum corneum, epidermis, basement membrane and dermis from the outside, and the dermis is the widest part of the area, and the cells are not packed as densely as the epidermis, rather there are more extracellular spaces. It is filled with a macromolecular network called the “extracellular matrix”. This extracellular matrix is produced in fibroblasts in the dermis and the like, and is composed of polysaccharides called acidic mucopolysaccharides such as hyaluronic acid and dermatan sulfate, and fibrous proteins such as collagen and elastin. Extracellular matrix is directly involved in skin elasticity, agitation, freshness, metabolism, etc. When the production of extracellular matrix in fibroblasts is dull, the elasticity and freshness of skin are lost, Wrinkles, wrinkles and rough skin are more likely to occur, contributing to skin aging.

The fibrous protein is mainly composed of collagen, of which type I collagen accounts for 80%. In addition to type I collagen, the presence of type III, V, XII, and XIV type collagen is known. One of the causes of wrinkles and sagging in aging skin is due to thinning of skin tissue with age. In aging skin, there is a significant decrease in collagen fibers, which are the main matrix component of the dermis, and this is likely the main cause of skin thickness reduction. Therefore, it is considered that promoting collagen production and maintaining the amount of collagen is effective in preventing and improving wrinkles and sagging.
In addition to the above, the promotion of collagen production is effective for improving wound healing of skin, treating osteoporosis, arthritis, tendonitis, etc., and preventing hypertension.

  On the other hand, the hyaluronic acid in the polysaccharide retains moisture in the cell gap, retains cells based on the formation of a jelly-like matrix in the tissue, retains the lubricity and flexibility of the tissue, mechanical failure, etc. It has many functions such as resistance to external force and prevention of bacterial infection. Recently, many studies have been conducted on the relationship with cancer metastasis. As a hyaluronic acid production promoter in fibroblasts and the like in the dermis, an extracellular matrix production promoter containing, for example, a bupreurum plant extract has been reported (for example, see Patent Document 1).

  Hyaluronic acid is also known to be produced in the epidermis (particularly epidermal basal cells) in addition to the production of fibroblasts in the dermis as described above, and promotes hyaluronic acid production that increases the amount of hyaluronic acid in the epidermis. Agents have also been reported (see, for example, Patent Documents 2 to 3).

  In addition to skin, hyaluronic acid is widely distributed in living bodies such as joint fluid, vitreous, ligament, etc. In addition to improving moisturizing effect, hyaluronic acid production promotes joint pain (degenerative knee joint disease) treatment, It is also effective in improving sagging, treating keratoconjunctival epithelial disorders, mainly dry eye, and maintaining the anterior chamber during cataract / corneal transplantation.

  In this way, collagen and hyaluronic acid can be applied to improve and prevent wrinkles, wrinkles, sagging skin, rough skin, and skin aging, as well as to improve knee arthritis and ophthalmic surgical preparations. If a substance capable of promoting the production of both collagen and hyaluronic acid can be found, there is an advantage that one substance can be widely applied to the above-mentioned symptom improvement, prevention and treatment.

WO99 / 17715 pamphlet Japanese Patent Laid-Open No. 9-176036 JP 2007-262012 A

  In view of the above conventional circumstances, the present invention provides a collagen production promoter, hyaluronic acid production promoter, and collagen production promotion and hyaluronic acid production promoter in mammals such as humans, which can be used safely and conveniently. For the purpose.

In order to solve the above-described problems, the present inventors have investigated the collagen production promoting action and hyaluronic acid production promoting action of human skin-derived fibroblasts and the hyaluronic acid production promoting action in human epidermis for various substances. As a result, it has been found that coronal acid has an extremely excellent effect of having both collagen production promoting action and hyaluronic acid production promoting action (production promoting action by both fibroblasts and epidermal cells). It came to be completed.
That is, according to this invention, the collagen production promoter which consists of a coronalic acid is provided.
Moreover, according to this invention, the hyaluronic acid production promoter which consists of a coronalic acid is provided.
Moreover, according to this invention, the collagen production promotion and hyaluronic acid production promoter which consist of a coronalic acid are provided.
Moreover, according to this invention, the collagen production promoter which consists of coronal acid, a hyaluronic acid production promoter, the foodstuff and skin external preparation which mix | blended the collagen production promoter and the hyaluronic acid production promoter are provided.
Coronalic acid is a compound having the structural formula of Chemical Formula 1 contained in the asteraceae xelanthemam (Tokiwana) seed oil, rice (Fukuyuki) and the like. As far as the inventors know, it has been reported so far that coronal acid has collagen production promoting activity or hyaluronic acid production promoting activity, and also has both collagen production promoting activity and hyaluronic acid production promoting activity. Absent.

Since the present invention has a high collagen production promoting effect and hyaluronic acid production promoting effect (production promoting effect by both fibroblasts and epidermal cells), external preparations for skin and oral compositions (for example, functional agents, foods and drinks) using the same Etc.), pharmaceutical preparations, etc. can be provided, which is useful for the treatment, prevention, improvement, etc. of various symptoms, diseases and pathologies involving collagen and hyaluronic acid. Specific application examples include, for example, improvement of rough skin, prevention and prevention of wrinkles, improvement of skin sagging, treatment of joint pain (degenerative knee osteoarthritis), treatment of keratoconjunctival epithelial disorder mainly for dry eye, cataract / corneal transplant surgery Examples include retention of the anterior chamber, improvement of skin wound healing, treatment of osteoporosis, arthritis, tendonitis, prevention of hypertension, and the like. However, application is not limited to these examples.

  Hereinafter, the present invention will be described in detail.

  The coronalic acid used in the present invention is sold as a reagent and can be purchased from Funakoshi Corporation.

    The collagen production promoter, hyaluronic acid production promoter, or collagen production promoter and hyaluronic acid production promoter of the present invention can be used in humans and animals by blending with a skin external preparation, as well as various foods and drinks, feeds (pets) It can be ingested by blending it with food, etc.). It can also be administered to humans and animals as a pharmaceutical formulation.

  When the collagen production promoter, hyaluronic acid production promoter, or collagen production promoter and hyaluronic acid production promoter of the present invention is added to the external preparation for skin, coronalic acid is 0.00001 to 10% by mass in the total amount of the external preparation, Preferably it is 0.00005-5 mass%. If the amount is less than 0.00001% by mass, the effect of the present invention is not sufficiently exerted. On the other hand, even if the amount exceeds 10% by mass, no further increase in effect can be expected. It tends to be difficult.

  When the present invention is applied to an external preparation for skin, in addition to the above components, components that are usually used in external preparations for skin such as cosmetics and pharmaceuticals within the range that does not impair the effects of the present invention, for example, antioxidants Oils, UV protection agents, surfactants, thickeners, alcohols, powder components, color materials, aqueous components, water, various skin nutrients, and the like can be appropriately blended as necessary.

  Furthermore, edetate disodium, edetate trisodium, sodium citrate, sodium polyphosphate, sodium metaphosphate, sequestering agents such as gluconic acid, preservatives such as methylparaben, ethylparaben, butylparaben, caffeine, tannin, Verapamil, tranexamic acid and its derivatives, licorice extract, grabrizine, hot water extract of karin fruit, various herbal medicines, tocopherol acetate, glycyrrhizic acid and its derivatives or salts thereof, vitamin C, magnesium ascorbate phosphate, Whitening agents such as ascorbic acid glucoside, arbutin, and kojic acid, and sugars such as glucose, fructose, mannose, sucrose, and trehalose can also be appropriately blended.

  The external preparation for skin can be applied to cosmetics and quasi-drugs applied to the outer skin, and particularly preferably can be widely applied to cosmetics. The dosage form can also be applied to the skin. Any dosage form such as solution system, solubilization system, emulsification system, powder dispersion system, water-oil two-layer system, water-oil-powder three-layer system, ointment, lotion, gel, aerosol, etc. is applicable. Is done.

  The use form is also arbitrary, and for example, it can be used for facial cosmetics such as lotions, emulsions, creams and packs, makeup cosmetics such as foundations, lipsticks and eye shadows, aromatic cosmetics, bath preparations and the like.

  In addition, makeup cosmetics can be widely applied to foundations and the like, and toiletries such as body soaps and soaps. Furthermore, if it is a quasi-drug, it can be widely applied to various ointment forms. And the form which can take the collagen production promoter of this invention, a hyaluronic acid production promoter, and a collagen promotion and a hyaluronic acid production promoter of this invention is not limited to these dosage forms and forms.

  When the collagen production promoter, hyaluronic acid production promoter, or collagen production promoter and hyaluronic acid production promoter of the present invention are blended in foods and drinks, feeds, etc., coronalic acids are their types, purpose, form, and method of use. For example, it can be about 0.0001 to 10% by mass in the total amount of food and drink. Preferably it is 0.001-5 mass%. In particular, when used as a health food or drink, it is preferable to contain the active ingredient of the present invention in such an amount that a predetermined effect is sufficiently exhibited.

  As a form of food-drinks or feed, it can be arbitrarily shaped into, for example, a granule, a granule, a paste, a gel, a solid, or a liquid. These include various known substances that are recognized to be contained in foods and drinks, such as binders, disintegrants, thickeners, dispersants, reabsorption accelerators, flavoring agents, buffers, and surfactants. Excipients such as solubilizers, preservatives, emulsifiers, tonicity agents, stabilizers and pH adjusters can be included as appropriate.

  When the collagen production promoter, hyaluronic acid production promoter, or collagen production promoter and hyaluronic acid production promoter of the present invention is used as a pharmaceutical preparation, the preparation is orally or parenterally (intravenous administration, intraperitoneal administration, etc. ) As appropriate. The dosage form is also arbitrary, for example, oral solid preparations such as tablets, granules, powders and capsules, oral liquid preparations such as internal liquids and syrups, and parenteral liquid preparations such as injections. These forms can also be appropriately prepared by known methods. For these pharmaceutical preparations, commonly used binders, disintegrants, thickeners, dispersants, reabsorption accelerators, corrigents, buffers, surfactants, solubilizers, preservatives, emulsifiers, isotonicity Excipients such as agents, stabilizers and pH adjusters may be used as appropriate.

  When the collagen production promoter, hyaluronic acid production promoter, or collagen production promoter and hyaluronic acid production promoter of the present invention is used as an external preparation for skin, food or drink, feed, pharmaceutical preparation, etc., various collagens and hyaluronic acid are involved. It is useful for treatment, prevention, improvement, etc. Specific application examples include, for example, improvement of rough skin, prevention and prevention of wrinkles, treatment of joint pain (degenerative knee osteoarthritis), improvement of skin sagging, keratoconjunctival epithelial disorder treatment mainly for dry eye, cataract / corneal transplant surgery It is suitably used for holding the anterior chamber, improving wound healing of the skin, preventing and treating osteoporosis, arthritis, tendonitis, etc., and preventing and treating hypertension. In addition, with the concept of physiological functions such as treatment, prevention, and improvement of the above symptoms, diseases, and pathological conditions, it should be applied to external preparations for skin, functional foods, foods for the sick, foods for specified health use, etc. Can do.

EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is not limited to a following example.
1. Preparation of coronal acid solution Coronal acid solution (Larodan)
The solvent of Fine Chemicals) was distilled off and dissolved in DMSO to prepare a 2% solution. This DMSO solution was used in the following experiment.
2. Measurement of collagen and hyaluronic acid production promoting effect (Example 1: Evaluation of type I collagen production)
Human fibroblasts were seeded in a 96-well plate at 1 × 10 4 cells / well in DMEM medium supplemented with 10% fetal bovine serum, and after 4 hours, the serum concentration was replaced with 0.5%. One day later, the medium was replaced with 0.5% serum-added DMEM medium supplemented with a predetermined concentration of coronal acid. On the fourth day after cell seeding, collagen in the culture supernatant was measured, and the amount of DNA in the cells was measured, which was used as an indicator of the number of cells.
The amount of collagen was measured by ELISA using a type I procollagen type I carboxyterminal propeptide (PIP) produced by human fibroblasts using a kit MK-101 manufactured by Takara Shuzo. The amount of PIP was converted per DNA. The amount of DNA was measured by a fluorescence measurement method using H33342 manufactured by Hoechst. The amount of PIP per DNA of the coronalic acid-added sample when the amount of PIP per DNA of the control to which only the solvent was added was 100 was defined as the collagen production promotion rate (%). The results are shown in Table 1.

(Example 2: Evaluation of dermal hyaluronic acid production)
Human fibroblasts were seeded in a 96-well plate at 1 × 10 4 cells / well in DMEM medium supplemented with 10% fetal bovine serum, and after 4 hours, the serum concentration was replaced with 0.5%. One day later, the medium was replaced with 0.5% serum-added DMEM medium supplemented with a predetermined concentration of coronal acid. On the 4th day after cell seeding, hyaluronic acid in the culture supernatant was measured, and the amount of DNA in the cells was measured and used as an index of the number of cells.
The amount of hyaluronic acid was measured using a hyaluronic acid measurement kit (manufactured by Chugai Pharmaceutical Co., Ltd.) and converted per DNA. The amount of DNA was measured by a fluorescence measurement method using H33342 manufactured by Hoechst. The hyaluronic acid production promotion rate (%) was the hyaluronic acid amount per DNA of the coronalic acid-added sample when the PIP amount per DNA of the sample not added with the extract (control) was 100. The results are shown in Table 2.

表１〜２の結果から明らかなように、本発明に用いられるコロナリックアシッドは、コラーゲン産生促進作用、ヒアルロン酸産生促進作用（線維芽細胞、表皮細胞の両者による産生促進作用）をすべて併せもつという極めて優れた効果があることが確認された。

As is clear from the results in Tables 1 and 2, the coronalic acid used in the present invention has both collagen production promoting action and hyaluronic acid production promoting action (production promoting action by both fibroblasts and epidermal cells). It was confirmed that there was an extremely excellent effect.

  Further formulation examples are shown below.

(Formulation example 1: lotion)
(Mixed component) (mass%)
Water residue Ethanol 10
Butylene glycol 7
Dipropylene glycol 5
Glycerin 2
Polyethylene glycol (PEG-6) 0.5
Polyethylene glycol (PEG-32) 0.5
Hydroxyethyl cellulose 0.1
This collagen production promoter (Coronalic acid) 0.01
Arginine 0.01
Izayoi Rose Extract 0.2
Hydrolyzed yeast extract 0.02
Sodium hyaluronate 0.01
Ichiyakuso Extract 0.2
Water-soluble collagen 0.2
Asenyaku extract 0.1
Polypropylene glycol-13decyltetradeceth-24 0.5
Sodium citrate 0.05
Sodium metaphosphate 0.05
Citric acid 0.05
Preservative appropriate amount Fragrance proper amount

(Formulation example 2: essence)
(Mixed component) (mass%)
(Phase A)
Water residue Glycerin 6
Ethanol 5
Dipropylene glycol 5
Polyethylene glycol / polypropylene glycol -14/7 dimethyl ether 3
Polyethylene glycol-400 1
Sodium polyacrylate 0.1
Xanthan gum 0.05
This hyaluron production promoter (Coronalic Acid) 0.02
Arginine 0.01
Isaiyo Rose Extract 0.1
Hydrolyzed yeast extract 0.2
Sodium hyaluronate 0.01
Ichiyakuso Extract 0.3
Water-soluble collagen 0.2
Asenyaku extract 0.1
Novara extract 0.2
Carboxyvinyl polymer 0.3
Butylene glycol 3
Potassium hydroxide 0.15
(Acrylic acid / alkyl acrylate (C10-30) copolymer 0.1
Sodium metaphosphate 0.03
(Phase B)
Cyclomethicone 2.5
Dimethicone 2
Polyethylene glycol-60 hydrogenated castor oil 0.5
Preservative appropriate amount perfume appropriate amount (production method)
The A phase and the B phase, which were uniformly dissolved, were mixed at room temperature and homomixed.

(Formulation formulation example 3: emulsion)
(Mixed component) (mass%)
(Phase A)
Water residue Butylene glycol 8
Ethanol 5
Dipropylene glycol 5
Glycerin 5
Dimethicone 2
2-Amino-2-methyl-1,3-propanediol (AMPD) 0.08
Carboxyvinyl polymer 0.15
EDTA-3Na 0.05
Xanthan gum 0.1
This collagen production promoter and this hyaluronic acid production promoter (Coronalic Acid) 0.005
Arginine 0.01
Izayoi Rose Extract 0.2
Hydrolyzed yeast extract 0.2
Sodium hyaluronate 0.05
Ichiyakuso Extract 0.3
Water-soluble collagen 0.2
Asenyaku extract 0.1
(Phase B)
Behenyl alcohol 0.4
Pentaerythrityl tetraethylhexanoate 5
Polyethylene glycol-60 hydrogenated castor oil 0.5
Hydrogenated polydecene 2
Hydrogenated palm oil 0.5
Batyl alcohol 0.4
Palm kernel oil 0.4
Palm oil 0.1
Preservative appropriate amount perfume appropriate amount (production method)
A phase (water phase part) and B phase (oil phase part) were each heated to 70 ° C. and completely dissolved. After adding A phase to B phase and stirring well, it emulsified with the emulsifier. The obtained emulsion was cooled using a heat exchanger.

(Formulation example 4: emulsion)
(Mixed component) (mass%)
(Phase A)
Water residue Glycerin 8
Ethanol 5
Dipropylene glycol 4
Hydrogenated polydecene 4
Polyethylene glycol-20 3
Carboxyvinyl polymer 0.09
Xanthan gum 0.05
Sodium metaphosphate 0.02
2-Amino-2-methyl-1,3-propanediol (AMPD) 0.03
This collagen production promoter (Coronalic acid) 0.01
Arginine 0.01
Izayoi Rose Extract 0.3
Hydrolyzed yeast extract 0.2
Sodium hyaluronate 0.01
Ichiyakuso Extract 0.3
Water-soluble collagen 0.5
Asenyaku extract 0.1
(Phase B)
Pentaerythrityl tetraethylhexanoate 3
Cetyl ethylhexanoate 2
Hydrogenated palm oil 2
Vaseline 1.5
Dimethicone 1
Polyethylene glycol stearate-5 glyceryl 1
Polyethylene glycol isostearate-60 glyceryl 1
Behenyl alcohol 0.5
Glyceryl diisostearate 0.4
Batyl alcohol 0.2
Preservative appropriate amount perfume appropriate amount (production method)
The A phase (aqueous phase part) and the B phase (oil phase part) were each heated to 70 ° C. and completely dissolved. After adding A phase to B phase and stirring well, it emulsified with the emulsifier. The obtained emulsion was cooled using a heat exchanger.

(Formulation example 5: Candy)
(Mixed component) (mass%)
Sugar 50
Minamata Residual Hyaluronic Acid Production Promoter (Coronalic Acid) 0.005
Fragrance 1

(Formulation Example 6: Tablet)
(Mixed component) (mass%)
Dextrin 31.6
Sucrose ester 4.7
Crystalline cellulose 4.9
Methylcellulose 2.4
Glycerol 1.7
This collagen production promoter and this hyaluronic acid production promoter (Coronalic Acid) 0.1
N-acetylglucosamine 13.3
Hyaluronic acid 10.0
Vitamin E 2.0
Vitamin B6 1.3
Vitamin B2 0.7
α-Lipoic acid 1.3
Coenzyme Q 2.7
Ceramide (konjac extract) 3.3
L-proline 20.0

(Formulation example 7: soft capsule)
(Mixed component) (mass%)
Edible soybean oil 42.08
Eucommia extract 3.3
Carrot extract 3.3
This collagen production promoter (Coronalic acid) 0.02
Royal Jelly 3.3
Maca 2.0
γ-aminobutyric acid (GABA) 2.0
Beeslow 4.0
Gelatin 25.0
Glycerin 8.0
Glycerin fatty acid ester 7.0

(Formulation example 8: soft capsule)
(Mixed component) (mass%)
Brown rice germ oil 77.1
This hyaluronic acid production promoter (coronalic acid) 0.1
Resveratrol 0.1
Lotus germ extract 6.7
Elastin 12.0
DNA 2.0
Folic acid 2.0

(Formulation example 9: granules)
(Mixed component) (mass%)
This collagen production promoter and this hyaluronic acid production promoter (Coronalic Acid) 0.1
Vitamin C 8.3
Soy isoflavone 20.8
Reduced lactose 58.3
Soybean oligosaccharide 3.0
Erythritol 3.0
Dextrin 2.5
Fragrance 2.0
Citric acid 2.0

(Formulation example 10: drink)
(Mixed component) (mass%)
Eucommia extract 3.2
Carrot extract 3.2
This collagen production promoter (Coronalic acid) 0.01
Reduced maltose starch syrup 56.0
Erythritol 16.0
Citric acid 4.0
Fragrance 2.6
N-acetylglucosamine 2.0
Hyaluronic acid 1.0
Vitamin E 0.6
Vitamin B6 0.4
Vitamin B2 0.2
α-Lipoic acid 0.4
Ceramide (konjac extract) 0.8
L-proline 4.0
Purified water residue

(Formulation Example 11: Cookie)
(Mixed component) (mass%)
Soft flour 48.98
Butter 17.5
Granulated sugar 20.0
Hyaluronic acid production promoter (Coronalic acid) 0.02
Egg 12.5
Fragrance 1.0
(Manufacturing method)
While stirring butter, granulated sugar was gradually added, and eggs, coronalic acid, and fragrance were added and further stirred. After sufficiently stirring, a weakly shaken flour was added, stirred at a low speed, and agglomerated and laid in a refrigerator. Then, it shape | molded and baked at 170 degreeC for 15 minutes, and was set as the cookie.

(Formulation Example 12: Ointment)
(Mixed component) (mass%)
The collagen production promoter and the hyaluronic acid production promoter (Coronalic Acid) 0.01
Stearyl alcohol 18.0
Owl 20.0
Polyoxyethylene (20) monooleate 0.25
Glycerin monostearate 0.3
Vaseline 40.0
Purified water residue (manufacturing method)
Purified water is kept at 70 ° C. (aqueous phase). The remaining components are mixed and dissolved at 70 ° C. (oil phase). An oil phase was added to the aqueous phase, and the mixture was uniformly emulsified with a homomixer and then cooled to obtain an ointment.

(Formulation Formulation 13: Patch)
(Mixed component) (mass%)
This hyaluronic acid production promoter (coronalic acid) 0.003
Crotamiton 3.2
Ester oil ("Panasate 875R") 2.5
Squalane 1.0
dl-camphor 0.07
Polyoxyethylene (60 mol) hydrogenated castor oil 1.2
Concentrated glycerin 5.0
Gelatin 1.2
Polyvinylpyrrolidone 0.6
Methyl paraben appropriate amount d-sorbitol solution 35.0
Aluminum hydroxide 0.2
Sodium sulfite appropriate amount Sodium edetate appropriate amount Citric acid appropriate amount Carboxyvinyl polymer 0.22
Sodium polyacrylate 0.24
Sodium carboxymethylcellulose 2.8
Kaolin 1.0
Purified water residue

It can be used for a collagen production promoter composed of coronalic acid, a hyaluronic acid production promoter, a food containing a collagen production promoter and a hyaluronic acid production promoter, and an external preparation for skin.

Claims (5)

  Collagen production promoter consisting of coronalic acid.   Hyaluronic acid production promoter consisting of coronalic acid.   A collagen production promoting and hyaluronic acid production promoting agent comprising coronalic acid. The foodstuff which mix | blended the production promoter in any one of Claims 1-3 The external preparation for skin which mix | blended the production promoter in any one of Claims 1-3