KR20110017599A - Composition for reducing skin pore size containing polyphenol compounds - Google Patents

Abstract

PURPOSE: A composition containing polyphenol compounds for pore tightening is provided to suppress complex formation of SNARE(soluble Nethylmaleimide-sensitive factor attachment protein receptor). CONSTITUTION: A composition for pore tightening contains 0.0001-30 weight% of polyphenol compounds as active ingredients. The polyphenol compounds are myricetin, quercetin, luteolin, delphinidin, cyaniding, butein, ellagic acid, EGCG(Epigallocatechin gallate), fisetin, derivative thereof. An external use skin composition contains the composition for pore tightening. The external use skin composition is a percutenous formulation. A pharmaceutical composition or cosmetic composition contains the composition for pore tightening.

Description

Composition for reducing pores containing polyphenol compounds {Composition for reducing skin pore size containing polyphenol compounds}

The present invention relates to a composition for shrinking pores containing a polyphenol compound as an active ingredient.

When the neurotransmitter is discharged, the synaptic vesicle containing the neurotransmitter must be fused with the presynaptic membrane to form a pathway between the two boundaries. The proteins that provide the cause of membrane fusion are three protein complexes called soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE). Membrane fusion between the synaptic vesicles and the synaptic membrane opens the neurotransmitter pathway, involving the t-SNARE complex attached to the target membrane and v-SNARE attached to the vesicle. T-SNARE is a complex of a protein called syntaxin 1a and a protein called SNAP-25. These SNARE proteins are twisted like pretzel. The membrane fusion results in rearrangement of the lipid bilayer, which is well known in the art. Biofilms are strongly pushed against each other, so these membranes are not spontaneously fused and have a strong force from outside to overcome the repulsion between the membranes. SNARE protein creates strong force that can overcome the repulsion between the membranes. In other words, the formation of the SNARE complex is a key phenomenon of exocytosis that overcomes the repulsion between membranes and releases neurotransmitters.

On the other hand, in order to control the relaxation and contraction of the muscle, there is a neuromuscular junction (neuromuscular junction) in the upper layer of the muscle, the nerve terminal (nerve terminal) is loaded with synaptic vesicles. Through the membrane fusion process by the SNARE protein as described above, the neurotransmitter in the synaptic vesicles loaded at the nerve terminal can be discharged to regulate the relaxation and contraction of the muscle.

The pores are distributed throughout the facial skin, but the nose and cheek area can be identified with the naked eye, and the appearance of the pores varies depending on the endogenous and exogenous factors such as sex, genetics, aging, acne and chronic UV exposure. The pores are widened because the sebum is excessively secreted or skin aging begins. As the collagen fibers and elastic fibers supporting the wall of the pores degenerate and decrease, the skin elasticity is lost and sagging.

On the other hand, since the contraction or relaxation of the muscles (hair muscles) attached to the hair is controlled by the sympathetic and parasympathetic nerves, the pores can be reduced or enlarged by neuromodulation. Sympathetic nerve is slightly away from the muscles pore shrinkage action, parasympathetic nerves are close to the muscles are pore enlargement action. Optionally, suppressing parasympathetic nerves causes the sympathetic nerve to act as a compensatory action, shrinking the muscles attached to the hair and shrinking the pores.

Accordingly, one aspect of the present invention, to find that the polyphenol compound directly reduces the pore size by inhibiting the action of the SNARE protein, to provide a composition for pore shrinkage using the same.

Provided is a pore reduction composition containing a polyphenol compound as an active ingredient.

The composition for reducing pores according to an aspect of the present invention may inhibit the formation of the SNARE complex and reduce the pores by inhibiting the release of neurotransmitters by the action of the SNARE complex. Moreover, it is non-toxic and safe using natural ingredients, has fewer side effects and less skin irritation.

One aspect of the invention relates to a composition containing a polyphenol compound. More specifically, one embodiment of the present invention is myricetin (myricetin), quercetin (quercetin), luteolin (luteolin), delphinidin (delphinidin), cyanidin (cyanidin), butein (butein), ellagic acid (ellagic acid) , EGCG (Epigallocatechin gallate), pisetin (fisetin) and derivatives thereof, including one or two or more combinations as an active ingredient, and inhibits the formation of SNARE complexes to provide a composition for shrinking pores that inhibit neurotransmitter release do. One preferred embodiment of the present invention provides a composition for shrinking pores comprising one or two or more combinations selected from myricetin, quercetin, delphinidine and cyanidin and derivatives thereof as an active ingredient. One more preferred embodiment of the present invention provides a composition for shrinking pores comprising one or two or more combinations selected from myricetin, delphinidin and derivatives thereof as an active ingredient.

Myricetin (myricetin) is a natural flavonol, the molecular formula is C ₁₅ H ₁₀ O ₈ , the molecular weight is 318.24, and has the structure of formula (1). 3,3 ', 4', 5,5 ', 7-hexahydroxyflavone (3,3', 4 ', 5,5', 7-hexahydroxyflavone), cannabiscetin, myricetol Also called myricitin. Tea, grapes, onions, broccoli, apples, grapes, etc. are mainly in the form of glycosides, and pure myricetin is a yellow-beige crystalline powder. Antioxidants, cancer prevention, antiviral, antidiabetic, antithrombotic efficacy and the like are known.

Quercetin (quercetin) is also a natural flavonol, the molecular formula is C ₁₅ H ₁₀ O ₇ , the molecular weight is 302.24, and has the structure of formula (2). It is an antioxidant to prevent food deterioration. It is widely used as a food additive and widely distributed in vegetables and fruits.

Delphinidin (delphinidin) is an anthocyanidins of vegetable pigments, the molecular formula is C ₁₅ H ₁₄ O ₇ , molecular weight is 306.27, and has the structure of formula (3). As an antioxidant, it is found in many blue and purple flowers.

Cyanidin is also an anthocyanidin which is a vegetable pigment, and the molecular formula is C ₁₅ H ₁₁ O ₆ +, the molecular weight is 287.24, and has the structure of Formula 4 below. As an antioxidant, it is found in red vegetables and fruits. Anti-inflammatory, cancer and cardiovascular disease prevention, obesity inhibitory effect and the like are known.

[Formula 1]

[Formula 2]

(3)

[Formula 4]

The polyphenol compounds constituting the active ingredient herein are free form (free acid or base form) and all prodrugs, polymorphs, hydrates, solvates, tautomers ( tautomers, stereoisomers, and the like, unless otherwise specified, it is to be understood to include all pharmaceutically acceptable forms as described above and to include all active forms of the compounds. It is also to be understood that suitable active metabolites (any suitable form) of such compounds are included here.

In the composition according to one aspect of the present invention, the polyphenolic compound inhibits the formation of SNARE to inhibit membrane fusion, and as a result, inhibits the release of neurotransmitters, especially acetylcholine, and inhibits the action of acetylcholine to nerve Impulses are disturbed and cause convulsive paralysis of muscle cells. Through such a process, the composition according to an aspect of the present invention may cause convulsive paralysis of the hair follicle cells around the pores and constrict pores.

Botulinum toxin is a substance that inhibits the release of acetylcholine and causes convulsive paralysis of muscle cells. However, botulinum toxin is a type of neurotoxin, known as one of the strongest toxins, with an average lethal dose of about 1 ng / kg (intravenous injection), which means that one teaspoon can kill 1.2 billion people. to be. Most of these botulinum toxin delivery methods are by injection technique, and inappropriate injection techniques can damage tissue and / or deliver botulinum toxin to an unintended and / or undesired location. In addition, in the area around the eyes, side effects such as lid and brow ptosis may occur, and pain, hematoma, ecchymosis and bruising may occur.

In the composition according to one aspect of the invention, the polyphenolic compound is nontoxic and safe, and also has high stability. Accordingly, the pore reduction composition of one embodiment of the present invention can be used as a transdermal dosage form as well as injection. The composition according to an embodiment of the present invention may include 0.0001 to 30% by weight, based on the weight of the total composition, a material selected from polyphenol compounds, and may also include 0.001 to 10% by weight, and 0.01 to 2% by weight. May contain%. If it is less than 0.0001% by weight it is difficult to show the efficacy, if it exceeds 30% by weight may be a concern of side effects. In one embodiment of the present invention, the polyphenol compound may achieve a pore reduction effect with little risk of side effects due to the influence of solubility.

One aspect of the present invention provides a cosmetic composition comprising a compound selected from polyphenol compounds. The cosmetic composition accordingly may for example be a cosmetic, the appearance of which contains a cosmetically or dermatologically acceptable medium or base. These are all formulations suitable for topical application, for example, emulsions, suspensions, microemulsions, microcapsules, microgranules or ionic (liposomes) obtained by dispersing the oil phase in solutions, gels, solids, pasty anhydrous products, aqueous phases, and It may be provided in the form of a nonionic vesicle dispersant or in the form of a cream, skin, lotion, powder, ointment, spray or cone stick. These compositions may be prepared according to conventional methods in the art. The composition according to the invention can also be used in the form of a foam or in the form of an aerosol composition further containing a compressed propellant.

Cosmetic compositions may include fatty substances, organic solvents, solubilizers, thickeners, gelling agents, emollients, antioxidants, suspending agents, stabilizers, foaming agents, fragrances, surfactants, water, ionic or nonionic emulsifiers, fillers Cosmetic or dermatology such as metal ion sequestrants, chelating agents, preservatives, vitamins, blockers, wetting agents, essential oils, dyes, pigments, hydrophilic or lipophilic actives, lipid vesicles or any other ingredients commonly used in cosmetics It may contain adjuvants commonly used in the art. Such adjuvants are introduced in amounts generally used in the cosmetic or dermatological arts.

Cosmetic composition according to an embodiment of the present invention is not particularly limited in the formulation, for example, softening longevity, astringent longevity, nourishing longevity, nutrition cream, massage cream, essence, eye cream, eye essence, cleansing cream It may be formulated into cosmetics such as cleansing foam, cleansing water, pack, powder, body lotion, body cream, body oil and body essence. The cosmetic composition according to an embodiment of the present invention may be applied in a form of being absorbed into the skin using a microneedle or the like. Cosmetic composition according to a preferred embodiment of the present invention may be applied in a transdermal dosage form, a skin coating form.

The present invention also provides a pharmaceutical composition comprising a compound selected from polyphenol compounds. Such pharmaceutical compositions may further contain pharmaceutical adjuvants such as preservatives, stabilizers, hydrating or emulsifying accelerators, salts and / or buffers for controlling osmotic pressure, and other therapeutically useful substances, and may be prepared in various oral forms according to conventional methods. It may be formulated in the form of a dosage form or parenteral dosage form.

The oral dosage forms include, for example, tablets, pills, hard and soft capsules, solutions, suspensions, emulsifiers, syrups, powders, powders, fine granules, granules, pellets, and the like, and these formulations include surfactants in addition to active ingredients. , Diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and glycine, and glidants such as silica, talc, stearic acid and its magnesium or calcium salts and polyethylene glycols. . Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidine, optionally starch, agar, alginic acid or its sodium salt Pharmaceutical additives such as disintegrants, absorbents, colorants, flavors, and sweeteners. The tablets can be prepared by conventional mixing, granulating or coating methods.

In addition, the parenteral administration agent may be, for example, formulations such as injections, drops, ointments, lotions, gels, creams, sprays, suspensions, emulsions, suppositories, and patches, but are not limited thereto. no.

The pharmaceutical composition according to an embodiment of the present invention may be administered orally, parenteral, rectal, topical, transdermal, intravenous, intramuscular, intraperitoneal, subcutaneous. The pharmaceutical composition according to one embodiment of the present invention may be administered topically to the facial skin, for example.

In addition, the pharmaceutically acceptable dose, ie dosage, of the active ingredient depends on the age, sex, and weight of the subject to be treated, the specific disease or pathology to be treated, the severity of the disease or pathology, the route of administration and the judgment of the prescriber. Will be different. The "pharmaceutically acceptable dose" refers to the amount generally applied in drug administration, and when used in such doses, is an amount that exerts efficacy at the active site of the subject without substantial severe toxicity, irritation, or allergic reactions. . Dosage determination based on these factors is within the level of skill in the art. Typical dosages can be from 0.01 mg / kg / day to 1000 mg / kg / day and from 1 mg / kg / day to 40 mg / kg / day, but the dosage limits the scope of the invention in any way. It is not.

Examples of the formulation of the composition according to the present invention are described below, but are also applicable to various other formulations, which are intended to explain in detail only and not intended to limit the present invention.

Formulation Example 1 Flexible Cosmetics

According to the composition shown in Table 1 below to prepare a flexible cosmetic water in a conventional manner.

TABLE 1

Compounding ingredient Content (% by weight) Polyphenolic compounds 0.01-2.0 glycerin 3.0 Butylene glycol 2.0 Propylene glycol 2.0 Carboxy Vinyl Polymer 0.1 Fiji-12 nonylphenyl ether 0.2 Polysorbate 80 0.4 ethanol 10.0 Triethanolamine 0.1 Preservative, coloring, fragrance Quantity Purified water Balance

Formulation Example 2 Nutritional Cosmetics

Nutritional longevity was prepared according to the composition described in Table 2 below in a conventional manner.

TABLE 2

Compounding ingredient Content (% by weight) Polyphenolic compounds 0.01-2.0 glycerin 3.0 Butylene glycol 3.0 Propylene glycol 3.0 Carboxy Vinyl Polymer 0.1 Beeswax 4.0 Polysorbate 60 1.5 Caprylic / Capric Triglycerides 5.0 Squalane 5.0 Sorbitassquioleate 1.5 Liquid paraffin 0.5 Triethanolamine 0.2 Preservative, coloring, fragrance Quantity Purified water Balance

Formulation Example 3 Nutrition Cream

Nutritional cream was prepared in a conventional manner according to the composition shown in Table 3.

[Table 3]

Compounding ingredient Content (% by weight) Polyphenolic compounds 0.01-2.0 glycerin 5.0 Butylene glycol 3.0 Liquid paraffin 10.0 Propylene glycol 3.0 Caprylic / Capric Triglycerides 5.0 Squalane 5.0 Fiji 60 Cured Castor Oil 2.0 Sorbitan sesquioleate 0.5 Polysorbate 60 1.5 Triethanolamine 0.2 Preservative, coloring, fragrance Quantity Purified water Balance

Formulation Example 4 Massage Cream

To prepare a massage cream in a conventional manner according to the composition described in Table 4.

[Table 4]

Compounding ingredient Content (% by weight) Polyphenolic compounds 0.01-2.0 glycerin 5.0 Butylene glycol 3.0 Liquid paraffin 40.0 Propylene glycol 3.0 Caprylic / Capric Triglycerides 4.0 Squalane 5.0 Fiji 60 Cured Castor Oil 2.0 Sorbitan sesquioleate 0.8 Polysorbate 60 1.5 Beeswax 10.0 Triethanolamine 0.2 Preservative, coloring, fragrance Quantity Purified water Balance

[Formulation Example 5] Pack

To prepare a pack in a conventional manner according to the composition described in Table 5.

TABLE 5

Compounding ingredient Content (% by weight) Polyphenolic compounds 0.01-2.0 glycerin 5.0 Sodium Carboxymethyl Cellulose 0.2 Polyvinyl alcohol 13.0 ethanol 6.0 Allantoin 0.1 Fiji 12 nonyl phenyl ether 0.3 Polysorbate 60 0.3 Preservative, coloring, fragrance Quantity Purified water Balance

Formulation Example 6 Ointment

The ointment was prepared in a conventional manner according to the composition described in Table 6.

TABLE 6

Compounding ingredient Content (% by weight) Polyphenolic compounds 0.01-2.0 glycerin 8.0 Butylene glycol 4.0 Liquid paraffin 15.0 Beta Glucan 7.0 Carbomer 0.1 Caprylic / Capric Triglycerides 3.0 Squalane 1.0 Cetearyl Glucoside 1.5 Sorbitan stearate 0.4 Cetearyl Alcohol 1.0 Beeswax 4.0 Preservative, coloring, fragrance Quantity Purified water Balance

Formulation Example 7 Injection

Polyphenolic Compound ................. 0.001-40 mg

Sterile Distilled Water for Injection ...

pH adjuster ...

According to the conventional method for preparing an injection, the amount of the above ingredient is prepared per ampoule (2 ml).

The present invention will be described in more detail with reference to the following examples and test examples. However, the following embodiments are merely preferred embodiments of the present invention, and the present invention is not limited to such embodiments.

Test Example 1 Membrane Inhibition Effect

The effects of membrane fusion inhibition on polyphenolic compounds were tested. To produce SNARE proteins, SNARE proteins called SNAP25 (NM011428), Trustsin 1a (AF217917) and VAMP2 (NM012663), respectively, were purified from biologically transformed E. coli Codon (+) RIL, Novagen. . First, palmitoyl oleoyl phosphatidylcholine (POP) (62 mol%), dioleoyl phosphatidylserine (DOPS) (35 mol%) 1-oleoyl-2- [N- (7-nitro-2,1,3-benzoxadiazol-4-yl) amino] caproyl phosphatidylserine (1-oleoyl-2- [N- (7-nitro -2,1,3-benzoxadiazol-4-yl) amino] caproyl phosphatidylserine; NBD-PS] (1.5 mol%) and the phosphorescent rhodamine (Rhodamin-PE, 1.5 mol%) were mixed and 10 mM liposomes (v -vesicle) and 50 mM liposomes were mixed by mixing DOPS and POPC at a molar concentration of 35:65 to produce liposomes that were not labeled with a fluorescent complex. In order to make a molar concentration of 1: 1 and mixed for 1 hour at room temperature, the fluorescent substance is not labeled liposomes and molar ratio 10 The mixture was mixed to 0: 1, and VAMP2 was combined with a liposome containing a fluorescent material so as to have a molar ratio of 50: 1.Then, the two types of liposomes were dialyzed while stirring at 4 ° C. for 24 hours using a 10 kDa dialysis membrane. After the process, the mixture was mixed at a ratio of 3: 7 (v-vesicle: t-vesicle), and then the methanol and polyphenol compounds, which were controls, were added to the mixture containing SNAP-25, trustsin 1a, and VAMP-2 at a concentration of 10 μM. Fluorescence intensity was measured using a fluorescence intensity measuring instrument (Model: SpectraMax M2, manufacturer: Molecular Device), and the results are shown in FIG. 1.

Since fluorescence intensity in FIG. 1 means membrane fusion between SNARE proteins, low fluorescence intensity indicates that membrane fusion was inhibited. The black circle represents the path through which the control reaction proceeds. As can be seen in Figure 1, the polyphenolic compound was found to have an effect of inhibiting the membrane fusion between SNARE proteins because the fluorescence intensity is lower than the control.

The fluorescence intensity of the control group was set as a reference and the relative membrane fusion inhibition rate (%) in the polyphenol compound was calculated. The results are shown in Table 7 below.

TABLE 7

compound Membrane Inhibition Rate (%) Control 100 EGCG (Epigallocatechin gallate) 88.76 ± 2.32 Butein 67.24 ± 1.32 Delphinidin 32.69 ± 0.32 Cyanidin 55.18 ± 1.73 Kaempferol 112.94 ± 5.32 Quercetin 65.62 ± 3.21 Myricetin 35.46 ± 4.23 Fisetin 52.27 ± 5.22 Luteline 81.96 ± 6.32 Ellagic acid 81.34 ± 1.32

As can be seen in Table 7, all polyphenol compounds except camphorol showed a membrane fusion inhibitory effect, and in particular, cyanidin, quercetin, and cecetin were 30% or more than control, and mycetin and delphinidine were 60% or more. It showed an inhibitory effect.

Experiment 2 Inhibitory Effect of Neurotransmitter Release on PC12 Cells

PC12 cells were cultured in a collagen coated plate (60 mm dish) in Ham's F12K medium containing 10% calf serum, 5% fetal bovine serum and antibiotics. Subculture was inhaled medium, pipet into 2 ml of PBS and pipetted to separate the cells from the dish wall, centrifuged at 1,000xg for 5 minutes to collect the cells, and then pipette with fresh medium to disperse the cell pellet. The plates were placed in fresh culture plates and incubated in an incubator at 37 ° C. and 5% CO ₂ gas supplied. [ ¹⁴ C] -acetylcholine used in the experiment was purchased from Amersham. After inhaling the medium from the plate of PC12 cells, PBS was added, the cells were removed from the plate wall, and the cell number was measured with a hematocytometer and dispersed in fresh medium at a concentration of 2 × 10 ⁵ cells / ml and inoculated. After 24 hours, acetylcholine assay buffer ([ ¹⁴ C] -Ach, 1 μCi / ml) was added and then introduced in a carbon dioxide incubator for 90 minutes. After the reaction, the buffer solution was removed, washed three times with PBS, and then reacted with a polyphenol compound (10 μM), L-type calcium channel inhibitor verapamil (vera μmil 10 μM), and botulinum toxin (2 nM) for 30 minutes. . After removing the medium, the high concentration of K ⁺ buffer was added, and then cultured in a carbon dioxide gas incubator for 12 minutes, and the supernatant was recovered to determine whether it inhibited the release of [ ¹⁴ C] -acetylcholine by a scintillation counter. It was confirmed whether the polyphenol compound inhibited the release of acetylcholine in PC12 cells by the above method, and the results are shown in FIG. 2.

As can be seen in Figure 2, all compounds except camphorol showed the inhibitory effect of acetylcholine release test, in particular myricetin, delphinidin, cyanidin, quercetin effectively inhibited, showed a similar level of inhibitory effect to botulinum toxin.

Test Example 3 Pore Size Analysis

10 men and women who feel facial pores are selected and prescribed according to Formulation Example 2 (0.1% of mycetin) .They apply to large areas of pores, mainly the nose and the surrounding skin, and leave for 10 to 15 minutes. It was applied once a day for 4 weeks in a light cleansing manner. Measurements were made by visual evaluation and instrument measurements before and after using the test product under constant temperature and humidity conditions. Visual evaluation was scored according to the degree felt by the person who participated in the test and shown in Table 8 below, skin pore size was measured using a pore size measuring device (Skin touch, in-house developed) and shown in Table 9 below.

[Table 8]

Viewpoint Pore condition (mean ± standard deviation) 2 weeks after the test 0.90 ± 0.74 4 weeks after the exam 1.70 ± 0.67 Determination of Effect
0: little effect, 1: slight effect, 2: much better, 3: fully satisfied

TABLE 9

Viewpoint Pore size (pixels, mean ± standard deviation) Before use 216 ± 53 2 weeks after the test 201 ± 54 4 weeks after the exam 193 ± 43

From the results of Table 8 and Table 9, it was confirmed that the composition according to an embodiment of the present invention has a pore size reduction effect.

Although the present invention has been described in connection with the above-mentioned embodiments, it is possible to make various modifications or variations without departing from the spirit and scope of the invention. Accordingly, the appended claims are intended to cover such modifications or changes as fall within the scope of the invention.

1 is a graph showing the effect of inhibiting the film fusion phenomenon by polyphenol compounds in one embodiment of the present invention.

Figure 2 is a graph showing the effect of inhibiting neurotransmitter release in PC12 cells by polyphenol compounds in one embodiment of the present invention.

Claims (9)

A composition for shrinking pores comprising a polyphenol compound as an active ingredient. According to claim 1, The polyphenol compound is myricetin (myricetin), quercetin (quercetin), luteolin (luteolin), delphinidin (cyaniding), butein (butein), ellagic acid (ellagic acid) acid), EGCG (Epigallocatechin gallate), pisetin (fisetin) and derivatives thereof. The composition of claim 2, wherein the polyphenol compound is one or two or more combinations selected from myricetin, quercetin, delphinidin, cyaniding, and derivatives thereof. The method of claim 1, wherein the active ingredient inhibits the formation of a complex of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) at the neuromuscular junction to inhibit membrane fusion to inhibit the release of neurotransmitters Reducing composition. The composition of claim 1, wherein the active ingredient comprises 0.0001 to 30 wt% based on the total weight of the composition. An external preparation composition for skin, comprising the composition of any one of claims 1 to 5. The external preparation composition for skin according to claim 6, wherein the composition is a transdermal dosage form. A pharmaceutical composition comprising the composition of any one of claims 1 to 5. Cosmetic composition containing the composition of any one of Claims 1-5.

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