KR101135285B1 - A composition for inhibiting hair loss or promoting hair growth containing ellagic acid or its derivatives - Google Patents

Abstract

The present invention relates to a composition for hair having hair growth-promoting or hair loss inhibiting efficacy containing ellagic acid or a derivative thereof. More specifically, the present invention relates to a composition capable of inhibiting hair loss and enhancing hair growth by effectively inhibiting apoptosis of keratinocytes in hair follicles caused by TGF-β by containing ellagic acid or a derivative thereof.

Ellagic acid, hair growth, hair loss prevention, TGF-β, hair follicle

Description

Composition for inhibiting hair loss or promoting hair growth containing ellagic acid or its derivatives}

1 is a graph showing the effect of ellagic acid inhibiting the function of TGF-β1 to inhibit the proliferation of human hair root cells.

2 is a graph showing the inhibitory effect of PAI-1 protein production according to the concentration of ellagic acid when TGF-β1 was treated to dermal papilla cells derived from rats.

3 is a graph showing the effect of inhibiting retrogression in the hair cycle of mice when treated with ellagic acid and minoxidil.

The present invention relates to a composition for hair having an effect of promoting hair growth or inhibiting hair loss containing ellagic acid or derivatives thereof, and the cell death of keratinocytes in hair follicles caused by TGF-β containing ellagic acid or its derivatives. The present invention relates to a composition capable of inhibiting hair loss by effectively inhibiting hair growth and promoting hair growth, and a method for promoting hair growth or inhibiting hair loss using such a composition.                         

Testosterone is involved in male sexual impulses, skeletal muscle increase, male external genitalia, scrotum growth, and spermatogenesis, among others. (dihydrotestosterone) is known to be involved (J. Invest. Dermatol. 1995; 105 (2): 209-14). Therefore, studies have been actively conducted to develop acne treatment agents, sebum secretion inhibitors and anti-hair loss agents by using the hormone inhibitors to inhibit the production of dihydrotestosterone.

On the other hand, in recent years, in addition to the male hormone that causes alopecia, the hair follicle cell death associated with alopecia is associated with TGF-β through a mixed culture experiment of hair follicle cells as a study on signal transduction substances after the hormone action. (FASEB J. 2002; 16 (14): 1967-9, J Investig Dermatol Symp Proc. 2003; 8 (1): 69-71).

Hydrangea macrophylla extract effectively inhibits TGF-β-induced protein (PAI-1) in hair follicle organ cultures. There is research showing that it promotes growth (J Investig Dermatol Symp Proc. 2003; 8: 65-68), procyanidin B-3 extracted from barley effectively inhibits the growth inhibition of mouse hair epithelial cells by TGF-β1, There is also a report that promotes the hair growth cycle of mice (Experimental Dermatology 2003; 11: 5362-541). In addition, research reports that phosphatidic acid and lysophosphatidic acid, known as phospholipids, effectively inhibit TGF-β1-induced degenerative hair cycle transduction by TGF-β1 through mitogen-activated protein kinase / extracellular signal-regulated kinase kinase (MEK) activation. (J Invest Dermatol 121; 448-456).

Elazic acid is a type of polyphenol widely distributed in the natural flora. 2,3,7,8-tetrahydroxy (1) benzopyrano (5,4,3-cde) (1) benzopyran-5,10- It may be represented by the following formula (1) as a compound named dione.

The ellagic acid (Ellagic acid) is a representative polyphenols well known as a hydrolysis product of tannin which is present in a large amount in natural plants, it is widely known to prevent cancer by eating a food containing ellagic acid. Elastic acid is active in anti-mutation studies and is known to inhibit the chemical-induced carcinogenesis of lung, liver, skin and esophagus in rodents. In addition, it is known that the skin of mice also has the effect of inhibiting the tumor by using TPA (J Cell Biochem Suppl., 1995; 22: 169-80).

Related patents for hair and skin application to the ellagic acid and its derivatives are known as follows.

Along with the well-known ATP-dependent Potassium Channel Opener such as minoxidil, ellagic acid or its salt has been applied for a patent that inhibits the production of phosphoserine residues of the hair keratin protein, thereby improving the properties of the hair surface (Japanese Patent Laid-Open No. 2001-302543).

In addition, ellagic acid or its derivatives are related to the use in skin-related cosmetics and pharmaceuticals, where elagic acid promotes the production of collagen VII in the extracellular matrix to enhance the junction between the epidermis and the dermis, thereby enhancing skin tone and wrinkles. And patent applications for improving hair condition (Publication Nos. US 20020098213, EP 1021161 and WO 99/016415).

However, the conventional use of ellagic acid for the skin and hair has been used only for improvement of the surface of the hair and the promotion of the production of extracellular matrix (collagen) in the skin as shown above, and induces hair growth or hair loss. No technique has been reported for preventing this.

Therefore, the present inventors have studied to find a method of inducing hair growth or preventing hair loss and various substances having such efficacy through various pathways.

As part of that effort, it is noted that Transforming Growth Factor-beta (TGF-β), known to have a function of inhibiting cell growth, is involved in hair follicle cell death associated with alopecia, Efforts were made to find substances that could effectively inhibit the hair follicle cell death-inducing function of TGF-β. As a result, it has been found that ellagic acid or derivative compounds thereof can effectively inhibit hair follicle cell death-inducing function of TGF-β to prevent hair loss and promote hair growth, thereby completing the present invention.

Accordingly, it is an object of the present invention to provide a composition which can contain ellagic acid or its derivatives to prevent hair loss and promote hair growth. Another object of the present invention is to provide a method for preventing hair loss and a method for promoting hair growth by using the ellagic acid or a derivative thereof.

It is also an object of the present invention to provide an inhibitor of TGF-β activity containing ellagic acid or a derivative thereof.

It is also an object of the present invention to provide a method for inhibiting hair follicle cell death and inhibiting retrogression in the hair growth cycle and a composition having such a function.

The present invention provides a composition for preventing hair loss or promoting hair growth containing ellagic acid or a derivative thereof.

The present invention also provides an inhibitor of TGF-β activity containing elazic acid or a derivative thereof. In addition, the present invention provides a method for preventing hair loss and a method for promoting hair growth using the ellagic acid or a derivative thereof.                     

The invention also provides methods of inhibiting hair follicle cell death and inhibiting retrogression in the hair growth cycle and compositions having such functions.

In the present invention, the derivative of ellagic acid includes both metal salt derivatives, amine salt derivatives, acyl group derivatives and sugar derivatives of ellagic acid. For example, salt derivatives such as sodium and calcium salts of ellagic acid, calcium salts and calcium salts including amine salts, and saturated or unsaturated acyl groups are bonded to ellagic acid, or sugars such as glucose in one or more hydroxyl groups are single or multiple ethers. All derivatives in bound form are included.

The composition containing the ellagic acid or its derivative is preferably an external preparation composition. Elastic acid or a derivative thereof in the composition acts in particular as an inhibitor of TGF-β activity.

In the composition, ellagic acid or a derivative thereof, which is an active ingredient, may be contained by 0.0001 to 10% by weight based on the total weight of the composition. If the content is less than 0.0001% by weight, it is difficult to show the activity of preventing hair loss or promoting hair growth, and the amount is also insufficient to show the effect of inhibiting TGF-β activity. In addition, even if the content is more than 10% by weight, it is preferable to limit the content as described above because the effect due to the content is weak or little.

The external preparation composition for preventing hair loss or promoting hair growth is not particularly limited in the formulation, hair tonic, scalft treatment, hair shampoo, hair cream, general ointment, soft cosmetics, nourishing cosmetics, eye cream, nutrition cream, massage cream, It may be formulated into a cleansing cream, cleansing foam, powder, and the like.                     

On the other hand, the composition according to the present invention can be used with minoxidil (minoxidil) or finasteride (finasteride) can maximize the effect. Accordingly, the present invention provides a composition for preventing hair loss or promoting hair growth, further comprising minoxidil or finasteride in addition to ellagic acid or a derivative thereof. It is natural that a composition containing the minoxidil or finasteride together with the ellagic acid or a derivative thereof may also be applied as a TGF-β activity inhibitor.

On the other hand, the composition containing ellagic acid or a derivative thereof according to the present invention can be used in combination with an oral administration type hair regrowth agent can enhance the hair loss prevention and hair regrowth effect. When used in combination with oral administration and external preparations as described above, it is possible to effectively prevent hair loss and promote hair growth by inhibiting the activity of TGF-β along with inhibiting the production of active male hormone. Examples of the orally administered hair regrowth drug include those produced by finasteride as an active ingredient.

Hereinafter, the present invention will be described more specifically.

Elazic acid and its derivatives known as 2,3,7,8-tetrahydroxy (1) benzopyrano (5,4,3-cde) (1) benzopyran-5,10-dione are conventionally mainly used in the skin as described above. TGF-β, which has been applied to improve the surface of hair by promoting the biosynthesis of the extracellular matrix collagen VII to improve wrinkles and inhibit the production of phosphoserine residues of the hair keratin protein, is known to induce direct hair loss in the present invention. It is not only applied to prevent hair loss by inhibiting the action of, but also used for inducing hair growth.

The function of such ellagic acid or derivatives thereof is found by the present inventors, and examples of the derivative of ellagic acid include, for example, metal salt derivatives including 1) sodium salt and calcium salt of ellagic acid; 2) amine salt derivatives consisting of methylglutamine, diethanolamine, triethanolamine, choline and bis-triethanolamine and amino acid salts; 3) Saturated or unsaturated acyl groups having 2 to 22 carbon atoms (e.g. acetic acid, palmitic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, stearic acid, brassidic acid, erucic acid, behenic acid and eicosane) Elazic acid derivatives bound thereto; And 4) derivatives in which sugars such as glucose are single or multiple ether bonded to one or more hydroxyl groups of ellagic acid.

The composition containing ellagic acid or a derivative thereof according to the present invention may be used in combination with a product (e.g., propesia) containing finasteride as an active ingredient that inhibits the production of active male hormone (DHT) as an external scalp external agent. At the same time, it inhibits the production of active male hormones that cause hair loss, and also inhibits hair follicle cell death mediated by active male hormones, thereby effectively preventing hair loss and maintaining or promoting hair growth. Such finasteride may be applied to the external preparation composition together with ellagic acid or a derivative thereof.

In addition, the addition of ellagic acid or its derivatives to the minoxidil drug, a vasodilator, among the commercially available hair regrowth drugs, prevents hair loss due to vasodilation and inhibits hair follicle cell death by TGF-β, leading to excellent hair loss and hair growth effects. You can expect.

Such ellagic acid or derivatives thereof may be appropriately selected and used by those skilled in the art without difficulty for hair loss prevention and hair growth effects as a raw material for improving hair growth.

When the present elazic acid and its derivatives are used for the purpose of preventing hair loss and promoting hair growth, 0.0001% to 10% by weight may be used with respect to the total weight of the composition, depending on the purpose and applied external preparation type. In consideration of the solubilization or formulation stability, it is preferable to use the content of 0.001% ~ 1%. When used in this range, it is most economical in terms of solubility and solubility of ellagic acid or its derivatives. If ellagic acid or its derivatives are not solubilized in certain formulations or have problems with stability, they may aggregate or denature in crystalline form and cause discoloration or odor.

Hereinafter, the present invention will be exemplarily described with reference to test examples, formulation examples, and the like.

Experimental Example 1 Inhibition of Proliferation of TGF-β in Epithelial Cells by Elazic Acid

In the control group treated with TGF-β at a concentration of 20 ng / ml on DMEM medium and the control group treated with ellagic acid at a concentration of 10 ug / ml on outer root sheath cells isolated from human hair follicles. Proliferation of each cell was confirmed by MTT staining.

Specifically, TGF-β1 (1ug / ml Roche, Swiss) was cultured after incubating 2000 cells per well in a 96-well plate incubator with isolated outer root sheath cells isolated from the posterior follicles of male volunteers. ) Was diluted in serum-free DMEM medium and treated with a concentration of 20 ng / ml in 200 μl of each ball as a control, and treated with a concentration of 10 ug / ml of ellagic acid (Sigma, USA) to the control group, respectively. After incubation for 3 days, the supernatant was removed, and the amount of insoluble formazan stain formed intracellularly by mitochondrial activity was confirmed by MTT staining.

The results are shown in FIG. As shown in Figure 1 it can be seen that by administering ellagic acid and its derivatives, it is possible to inhibit the action of TGF-β1 inhibits the proliferation of appearance myocytes. TGF-β1 (20ng / ml) was promoted by the cell death of human superficial myocytes as described above, 10ppm ellagic acid effectively prevented the induction of cell death.

Experimental Example 2 Inhibitory Effect of Elazic Acid on TGF-β Induced PAI-1 Protein Production

In the control group treated with TGF-β at a concentration of 5 ng / ml on DMEM medium using dermal papilla cells derived from rat whiskers, and the test group treated with ellagic acid at a concentration of 10 ug / ml on the control group, eluted with media. PAI-1 protein was quantified.

Specifically, 1 ml of DMEM medium at the concentration of 5 ng / ml TGF-β1 in a 24-hole plate culture plate of dermal papilla cells (Wendy Filsell et al., J Cell Sci, 107: 1761-1772, 1994) Treated in the control group, and treated with a concentration of ellagic acid (Sigma, E2250, USA) 10ug / ml in each of the control group incubated for 2 days, and then the supernatant was collected and eluted to the medium The resulting PAI-1 protein was quantified using a PAI activity assay kit (Chemicon, ECM 610).

The results are shown in FIG. The effect of ellagic acid inhibits PAI-1 protein production in TGF-β-treated dermal papilla cells.

Experimental Example 3 Inhibitory Effect of Elazic Acid on the Retrograde Entry of Mice

After waxing the back of female C57bl / 6 mice, 49 days of age, from the newly entered growing stage to the degenerative stage. After entering the growing follicular cycle, the negative control group is propylene glycol / ethanol / water. 3 groups of 8 mice each for 10 days, applying a solution consisting of 5/3/2, dissolving ellagic acid in a negative control solution at a concentration of 0.5% with 3% minoxidil as a positive control. Was applied.

In order to observe intradermal hair follicles, we evaluated the degenerative induction inhibitory effect of ellagic acid by setting the degenerative index by classifying the grade into 1-6 according to the degree of entry into each degenerative stage after the mouse biopsy.

The results are shown in Fig. Morphological observations of hair follicles in the skin, such as the positive control minoxidil solution, effectively inhibited the induction of the degenerative phase. As can be seen in Figure 3 it can be seen that the use of ellagic acid and minoxidil at the same time can suppress the entry of the retrograde phase in the hair growth cycle of the mouse.

Formulation examples are described below. The following formulation examples will be apparent to those skilled in the art.

Formulation Example 1 Formulation Example of Hair Tonic Containing Elastic Acid

ingredient Content (% by weight) ethanol 55 Castor oil 5 glycerin 3 Pyrotonolamine 0.1 Ellagic acid 1.0 Spices A reasonable amount Purified water balance system 100

Formulation Example 2 Formulation Example of Hair Lotion Containing Elastic Acid

ingredient Content (% by weight) Cetostearyl alcohol 2.0 Stearyl Triethyl Ammonium Chloride 2.0 Hydroxyethyl cellulose 0.5 Pyrotonolamine 0.1 Ellagic acid 1.0 Spices A reasonable amount Purified water balance system 100

Formulation Example 3 Formulation Example of Hair Nutrients Containing Elastic Acid

ingredient Content (% by weight) Beeswax 4.0 Polysorbate 60 1.5 Sorbitan sesquioleate 0.7 Liquid paraffin 5.0 Squalane 5.0 Caprylic / capric triglyceride 5.0 glycerin 3.0 Butylene glycol 3.0 Propylene glycol 3.0 Carboxy Vinyl Polymer 0.1 Triethanolamine 0.2 Ellagic acid 0.5 antiseptic A reasonable amount Spices A reasonable amount Purified water balance system 100

Formulation Example 4 Formulation Example of Minoxidil with Elazic Acid

ingredient Content (% by weight) Minoxidil 3 Propylene glycol 20 Sodium bisulfate 0.5 Ellagic acid 0.5 Pigment A reasonable amount ethanol 40 Purified water balance system 100

Formulation Example 5 Oral Finasteride Formulation Example (1mg Prescription Percentage)

ingredient Content (% by weight) Finasteride 5 Microcrystalline cellulose 42.5 Sod. starch glycolate 4.0 Mg. stearate 0.5 Fumed silica 0.5 lactose 47.5 system 100

<Example 1> Use of ellagic acid-containing hair tonic in combination with oral finasteride

Formulation Example 5, which contains 1 mg of finasteride drug, which is a human consumption, has a function of inhibiting the production of active male hormone dihydrotestosterone (DHT) from 5 testosterones through blood through 5 alpha-reductase. DHT, a male hormone, produces TGF-β in hair follicles and has no function to prevent hair follicle cell death. Therefore, by administering orally administering Formulation Example 5, and using elagic acid-containing hair tonic (Formulation Example 1) that inhibits the activity of TGF-β as an external preparation, effective hair loss prevention and hair growth can be induced. .

The composition containing ellagic acid or a derivative thereof according to the present invention can be used for preventing hair loss or promoting hair growth, and can also be applied as an inhibitor of TGF-β activity by inhibiting TGF-β activity. In addition, it is possible to suppress hair follicle cell death by using the ellagic acid or a derivative thereof, and to prevent hair loss and prevent hair loss by inhibiting the entry of the degenerative phase in the hair growth cycle.

Claims (11)

Contains elazic acid or a derivative thereof, The ellagic acid derivative may be a sodium salt, calcium salt and amine salt derivative of ellagic acid, an eladic acid derivative having a saturated or unsaturated acyl group having 2 to 22 carbon atoms, or a single or multiple ether bond of glucose to one or more hydroxyl groups of the ellagic acid. Hair loss prevention or hair growth promoting composition is selected from the group consisting of derivatives. The composition of claim 1, wherein the prevention of hair loss or the enhancement of hair growth is attributable to inhibition of TGF-β activity of the ellagic acid or a derivative thereof. delete The composition of claim 1, wherein the ellagic acid or a derivative thereof is contained in an amount of 0.0001 to 10% by weight based on the total weight of the composition. The composition of claim 1, wherein the composition has a hair tonic, a scalp treatment, a hair shampoo, a hair cream, a general ointment, a softening lotion, a nourishing longevity, an eye cream, a nourishing cream, a massage cream, a cleansing cream, a cleansing foam or a powder formulation A composition, characterized in that. The composition according to any one of claims 1, 2, 4 and 5, which further contains minoxidil or finasteride. A cosmetic composition for inhibiting hair follicle cell death by TGF-β containing ellagic acid of claim 1 or a derivative thereof. An external preparation composition for preventing hair loss or promoting hair growth containing the ellagic acid of claim 1 or a derivative thereof; And Oral dosage forms Regrowth set comprising a. The set according to claim 8, wherein the orally administrable hair regrowth composition comprises finasteride as an active ingredient. delete delete

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