KR20100085562A - Agents for skin whitening containing propafenone - Google Patents

Abstract

PURPOSE: A skin whitening composition containing propafenone is provided to suppress melanogenesis and pigmentation without side effects. CONSTITUTION: A skin whitening composition contains propafenone as an active ingredient. The composition is a cosmetic composition for skin whitening. The cosmetic composition is used in the form of solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, or spray.

Description

Agents for skin whitening containing Propafenone

The present invention relates to a composition for skin whitening, and more particularly, a composition for skin whitening comprising propaphenone, which has excellent product stability, can be safely used without side effects on the skin, and inhibits melanin production and has excellent pigmentation inhibitory effect. It is about.

The present invention relates to a composition for skin whitening, and more particularly, a composition for skin whitening comprising propaphenone, which has excellent product stability, can be safely used without side effects on the skin, and inhibits melanin production and has excellent pigmentation inhibitory effect. It is about.

Human skin color is determined by the concentration and distribution of melanin in the skin. In addition to genetic factors, it is also influenced by environmental or physiological conditions such as sun ultraviolet rays, fatigue and stress. Melanin pigment produced by melanocytes of human skin is a phenolic polymer having a complex form of black pigment and protein, and plays an important role in preventing skin damage caused by ultraviolet rays. In melanin biosynthesis, the action of tyrosinase in melanocytes is reported to be the most important. Tyrosinase plays a key role in the skin blackening process by converting tyrosine, an amino acid, into dopa and dopaquinone, intermediates of melanin polymer production. However, although the pathway by which melanin is made is known, it is still not clear what mechanisms induce melanin synthesis, the previous step in which tyrosinase works.

When such synthesis of melanin occurs excessively in the skin, it may darken the skin tone and cause blemishes and freckles. Therefore, by inhibiting the synthesis of melanin pigment in the skin, not only can brighten the skin tone to realize skin whitening, but also improve skin hyperpigmentation such as spots, freckles, etc. caused by ultraviolet rays, hormones and genetic causes. have.

Therefore, conventionally, substances having inhibitory activity against tyrosinase such as hydroquinone, ascorbic acid, kojic acid, and glutathione are used to prevent skin whitening or hyperpigmentation. Improved. However, hydroquinone exhibits a predetermined whitening effect but severe skin irritation has a problem of limiting the blending amount to a very small amount. Ascorbic acid is easily oxidized, and the cosmetics containing it are discolored and discolored. Acid is unstable in solution, which complicates the manufacturing process of cosmetics. In addition, thiol-based compounds such as glutathione and cysteine not only have a characteristic unpleasant odor, but also have problems with transdermal absorption, and glycosides and derivatives thereof have high polarity, making it difficult to use as a cosmetic ingredient. In addition, vitamin C has a problem in that it is easily oxidized in the aqueous solution state does not have a lasting effect. Accordingly, in recent years, compositions for skin whitening including natural herbal extracts have been developed, but most of them have color problems, and there is a problem in formulation, and the active ingredients have not been identified.

We will discover new whitening materials with excellent human safety and effectiveness and develop them into cosmetic compositions and pharmaceutical compositions.

One object of the present invention is to provide a composition for skin whitening comprising propaphenone.

Another object of the present invention to provide a cosmetic composition for skin whitening comprising the composition.

Another object of the present invention to provide a pharmaceutical composition for skin whitening comprising the composition.

According to the present invention, propofenone has a higher melanin production inhibitory effect than vitamin C, which is a main component of the existing whitening agent. In addition, no toxicity or irritation occurred in human safety tests, which proved to be safe for human use. Therefore, the propofenone of the present invention can be usefully used in cosmetics, medicine or food for skin whitening.

In one embodiment, the present invention relates to a composition for skin whitening comprising propafenone.

The IUPAC name of propafenone of the present invention is 1- {2- [2-hydroxy-3- (propylamino) propoxy] phenyl]}-3-phenylpropa-1-non (1- {2 -[2-hydroxy-3- (propylamino) propoxy] phenyl} -3-phenylpropan-1-one) and has the structure of Formula 1.

The propofenone of the present invention may be prepared by chemical synthesis, or may be a commercially prepared product (eg, propafenone from Sigma).

In order to examine the whitening effect of the propafaphenone of the present invention, compared with vitamin C (vitamin C) which is used as a conventional whitening cosmetic raw material, the activity of inhibiting intracellular tyrosinase activity and melanin production generally used for screening of whitening substances was measured. As a result, the propafenone of the present invention at the same concentration was more than about 50% more melanogenesis inhibitory effect than vitamin C. Therefore, the propaphenone of the present invention is excellent in the whitening effect.

Propaphenone of the formula (1) of the present invention includes derivatives exhibiting a skin whitening effect by inhibiting melanin production and / or tyrosinase activity of the derivatives obtained by addition or substitution reaction of substituents commonly practiced in the art. It is apparent to those skilled in the art in view of the level of skill in the art.

In the skin whitening composition of the present invention, the amount of propaphenone is preferably 0.001 to 10% by weight based on the total composition. When the amount is less than 0.0001% by weight, the whitening effect is too weak. When the amount is more than 15% by weight, the increase in effect due to the increase of the content is insufficient and the stability of the formulation is not secured. More preferably propaphenone is included in an amount of 0.001 to 5% by weight based on the total composition.

As another aspect, the present invention relates to a cosmetic composition for skin whitening comprising the composition.

The cosmetic composition includes ingredients conventionally used in cosmetic compositions in addition to propaphenone as an active ingredient, and includes, for example, conventional auxiliaries and / or carriers such as antioxidants, stabilizers, solubilizers, vitamins, pigments and perfumes. Include. In addition, the cosmetic composition may further include a skin absorption promoting material to enhance the skin whitening effect.

The cosmetic composition of the present invention may be prepared in any formulation commonly prepared in the art, for example, solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, surfactant-containing cleansing , Oils, powder foundations, emulsion foundations, wax foundations and sprays, and the like, but are not limited thereto. More specifically, it can be manufactured in the form of a soft lotion, a nutritional lotion, a nutritional cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray or a powder.

When the formulation of the present invention is a paste, cream or gel, animal oils, vegetable oils, waxes, paraffins, starches, trachants, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicas, talc or zinc oxide may be used as carrier components. Can be.

When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used, in particular, in the case of a spray, additionally chlorofluorohydrocarbons. Propellant such as propane / butane or dimethyl ether.

When the formulation of the present invention is a solution or an emulsion, a solvent, a dissolving agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.

When the formulation of the present invention is a suspension, liquid carrier diluents such as water, ethanol or propylene glycol, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystals Soluble cellulose, aluminum metahydroxy, bentonite, agar or tracant and the like can be used.

When the formulation of the present invention is a surfactant-containing cleansing, the carrier component is an aliphatic alcohol sulfate, an aliphatic alcohol ether sulfate, a sulfosuccinic acid monoester, isethionate, an imidazolinium derivative, a methyltaurate, a sarcosinate, a fatty acid amide. Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters and the like can be used.

In the cosmetic composition of the present invention, the amount of propaphenone may be included in an amount of 0.001 to 10% by weight, preferably 0.001 to 5% by weight based on the total composition.

In another aspect, the present invention relates to a pharmaceutical composition for skin whitening comprising the composition.

In the pharmaceutical composition of the present invention, the amount of propaphenone may comprise 0.001 to 10% by weight, preferably 0.001 to 5% by weight based on the total composition.

The pharmaceutical compositions of the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.

Formulations of the pharmaceutical compositions of the present invention include powders, granules, tablets, capsules, suspensions, emulsions, syrups, oral formulations such as aerosols, external preparations such as ointments, creams, suppositories, sterile injectable solutions, etc. It may be used in any form suitable for pharmaceutical formulations, including.

The pharmaceutical composition according to the present invention can be administered to mammals such as rats, mice, livestock, humans by various routes such as parenteral, oral, and all modes of administration can be expected, for example, oral, It may be administered by rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection. At this time, as a parenteral route, transdermal administration is preferred, and topical application is most preferred.

The dosage of the preparation varies depending on the subject's age, sex, weight, symptoms, and method of administration, but in the case of external preparations, 1.0 to 3.0 ml per day may be applied 1 to 5 times a day to continue for more than one month. .

In addition, the oral dosage form may vary depending on the age, sex, and weight of the patient, but the amount of 0.1 to 100 mg / kg may be administered once to several times a day. The dosage may also be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, and the like. Thus, the dosage amounts are not intended to limit the scope of the invention in any manner.

On the other hand, in a specific embodiment of the present invention, the cumulative skin irritation test results for propaphenone was found to be a natural substance harmless to humans. Therefore, the propofenone of the present invention has little toxicity and side effects, so that it can be used safely even when used for a long time, and in particular, it can be safely applied to cosmetic compositions and pharmaceutical compositions as described above.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited thereto.

Example  One : On propaphenone  By B16 Melanoma  Determination of melanin production inhibitory effect on cells

B16 melanoma cells were used to measure the inhibitory effect of melanin production by propapenone (Sigma), which was compared with the melanin production inhibitory effect of vitamin C, which is known to inhibit melanogenesis.

In this experiment, murine melanoma (B-16 F10) cells were inoculated at 1 × 10 ⁵ per well in a 6-well plate with DMEM medium containing 10% FBS (fetal bovine serum), followed by 5% CO _2. And The cells were cultured at 37 ° C. until the cells adhered at least about 80% to the bottom of the well. Processing the removed and then the culture medium was diluted to a suitable concentration of the sample medium, and cultured 3 days under 5% CO _2, 37 ℃. The concentration range of propafenone was determined to be 1 uM, 10 uM, 50 uM without cytotoxicity. The cells from which the medium was removed were washed with phosphated buffer saline (PBS) and treated with trypsin to recover the cells. The recovered cells were measured using a hematocytometer, and then divided into 2 mL tubes with the same number of cells in each treatment group. The cell pellet was dried at 60 ° C., and 100 μl of 1M sodium hydroxide solution containing 10% DMSO was added to obtain intracellular melanin in a 60 ° C. thermostat. Using this solution, the absorbance was measured at 490 nm using a microplate reader to determine the amount of melanin per cell. The results are shown in Table 1 below.

sample Treatment Concentration (uM) Melanin production inhibition rate (%) Vitamin c One 0 Vitamin c 5 0 Vitamin c 10 2 Propaphenone One 4 Propaphenone 5 52 Propaphenone 10 60

As shown in Table 1 above, at the same treatment concentration, propapenone showed better melanin production inhibition than vitamin C.

Example  2 : On propaphenone  by Melanin  Determination of melanin production inhibitory effect on cells

Human melanocytes (melanocytes) were used to measure the inhibitory effect of melanin production by propapenone and compared it with the inhibitory effect of intracellular tyrosinase activity by vitamin C, which is known to inhibit melanogenesis.

In this experiment, human epidermal melanocyte (neonatal) cells purchased from Cascade Biologics were cultured in Medium 254 medium containing Human Melanocyte Growth Supplement, also purchased from the same company. Human epidermal melanocytes were inoculated into 6-well plates at 1 × 10 ⁵ per well and incubated at 5% CO _{2 and} 37 ° C until the cells adhered to the bottom of the well at least 80%. After incubation, the medium was removed, the sample was diluted to an appropriate concentration and treated in the medium, and then cultured for 5 days while changing the medium once every two days under 5% CO _{2 ,} 37 ° C. The concentration range of propafenone was determined to be 1 uM, 5 uM, 10 uM without cytotoxicity. After the treatment, the medium was removed, washed with PBS (phosphated buffer saline), and then treated with trypsin to recover the cells. The recovered cells were measured using a hematocytometer, and then divided into 2 mL tubes with the same number of cells in each treatment group. The cell pellet was dried at 60 ° C., and 100 μl of 1M sodium hydroxide solution containing 10% DMSO was added to obtain intracellular melanin in a 60 ° C. thermostat. Using this solution, the absorbance was measured at 490 nm using a microplate reader to determine the amount of melanin per cell. The results are shown in Table 2 below.

sample Treatment Concentration (uM) Melanogenesis inhibition rate (%) Vitamin c One 0 Vitamin c 5 One Vitamin c 10 5 Propaphenone One 18 Propaphenone 5 26 Propaphenone 10 49

As shown in Table 2, at the same treatment concentration, the propane phenone showed a higher inhibitory rate of inhibition of intracellular melanin production than vitamin C.

Example  3: Evaluation of the whitening effect at the animal level

Similar to humans, the whitening effect of propaphenone was measured using brown maltomo (Tortoiseshell guinea pigs; Brown guinea pigs), which are known to cause pigmentation by ultraviolet rays.

In order to cause pigmentation due to ultraviolet (UV) in the brown molemoto, a light shielding aluminum foil having a square window of 3 × 3 cm ² is adhered to the skin from which the hair of the brown molemoto coordination is removed, and then SE lamp ( Ultraviolet rays were irradiated with a wavelength of 290-320 nm (Toshiba) (total irradiation energy amount = 1350 mJ / cm ² ). After UV irradiation, the aluminum foil was peeled off and a sample (propaphenone and vitamin C) was applied in the following manner. Pigmentation appeared 2 or 3 days after the UV irradiation, and reached a peak after about 2 weeks, and each sample was applied therefrom.

The number of coatings was continued once or twice a day for 50 days. Samples were dissolved and diluted with a specific solvent (Propylene Glycol: Ethanol: Water = 5: 3: 2 mixed solvent), coated with a cotton swab, and prepared a control site for necessarily applying a solvent to other sites. Along with the determination of effects, the cumulative stimulus was also observed.

The effect was determined by measuring the degree of black and white of the skin using a color difference meter (Minolta CR2002 chromameter), the results are shown in Table 3 below. L ^* A ^* B ^* color system is used to display color, and L ^* value was used as an index in this invention. L ^* value was calibrated with a standard whiteboard, and L ^* value was measured 5 times or more at one site, and pigmentation was equalized. The difference (ΔL ^* ) of the skin color at the start of application and at the end of application was determined and the effect was determined using this value. The results are shown in Table 3 below.

(Equation 1)

△ L ^* = L ^* value after 00 days application - L ^* value of the coating start date

Comparing the ΔL ^* value with respect to the sample application site and the control site, the effect of the whitening material can be seen.

sample Treatment Concentration (%) Whitening effect (△ L) Propaphenone 0.2 0.51 Propaphenone 1.0 0.59 Vitamin c 1.0 0.48 Control 0.35

As shown in Table 3 above, propapenone showed a superior whitening effect than vitamin C, and cumulative stimulation was not observed during the test application of the test substance, and thus safety was also excellent.

Example 4 Safety Confirmation Experiment of Propafenone on Human Skin

4-1. Preparation of external skin preparations including propaphenone

In order to confirm that propaphenone, which was found to be excellent in whitening effect as described above, is safe for human skin, an external skin preparation containing propaphenone and vitamin C was prepared and skin safety verification experiments were performed.

The external preparation for skin containing propaphenone and vitamin C was prepared by the ingredient contents of Table 4 below. In the following Table 4, the control group is an external skin preparation that does not include a tyrosinase inhibitor, and test group 1 and test group 2 are external skin preparations including propaphenone and vitamin C, respectively.

For the preparation of external skin preparations, purified water, glycerin and butylene glycol were mixed and dissolved at 70 ° C. (aqueous part), and the other components except the above three components and trimethanolamine were dissolved at 70 ° C. (oil phase part). The oil part was added to the water part and stirred with a homomixer (Tokushu Kika, Japan) to emulsify first, to which trimethanolamine was finally added. After removing the bubbles generated in the mixed solution, and cooled to room temperature to prepare a skin external preparation.

ingredient content (%) Control Test group 1 Test group 2 Purified water 72 72 72 glycerin 8.0 8.0 8.0 Butylene glycol 4.0 4.0 4.0 Propaphenone 0 1.0 0 Vitamin c 0 0 1.0 Caprylic Capri Triglyceride 8.0 8.0 8.0 Squalane 5.0 5.0 5.0 Cetearyl Glucoside 1.5 1.5 1.5 Sorbitan stearate 0.4 0.4 0.4 Cetearyl Alcohol 1.0 1.0 1.0 Trimethanolamine 0.1 0.1 0.1 Gross weight 100 100 100

4-2. Skin accumulation stimulation test

Whether or not propaphenone stimulates the skin by subjecting the upper forearm to a total of nine 24-hour cumulative patches every other day for 30 healthy adults using each skin preparation prepared in Example 4-1 Whether or not was measured.

The patch method used the fin chamber (Finn chamber, Epitest Ltd, Finland). 15ul of each said skin external preparation was dripped at the chamber, and the patch was performed. The degree of response to the skin each time was scored using the following formula, and the results are shown in Table 5 below.

(Equation 2)

Average responsiveness = [[response index x responsiveness / total number of subjects x highest score (4 points)] x 100] ÷ number of tests (9 times)

At this time, ± 1 point, + 2 points, + + 4 points in the reaction degree, and the average response was determined to be a safe composition when less than 3.

Test substance Number of subjects with response Average reactivity 1 week 2 weeks 3 weeks Primary Secondary 3rd 4th 5th 6th 7th 8th 9th ± + + + ± + + + ± + + + ± + + + ± + + + ± + + + ± + + + ± + + + ± + + + Control One - - --- --- --- --- --- --- --- --- 0.09 Test group 1 One - - One - - --- --- --- --- --- --- --- 0.13 Test group 2 One - - One - - --- --- --- --- --- --- --- 0.13 Inspector 30 30 30 30 30 30 30 30 30

In Table 5, in Test Group 1, the number of people corresponding to ±, +, and ++ was 1, 0, and 0, respectively, and the rest did not appear. When calculated according to the above-described formula, it was determined that the composition was [(1x2) / (20x4)] x100 / 9 = 0.13 with an average reactivity of 0.37 or less and 3 or less.

As shown in Table 5, the external skin preparations containing propaphenone (test group 1) did not show a distinct cumulative stimulation pattern as the external skin preparations including the control group or vitamin C and was determined to be a safe substance for human skin.

Examples of formulations for the composition of the present invention are illustrated below.

Formulation Example 1  Cosmetic preparations

1. Flexible cosmetics (content: wt%)

Propofenone 0.01

Glycerin 3.0

Butylene Glycol 2.0

Propylene Glycol 2.0

Carboxy Vinyl Polymer 0.1

Ethanol 10.0

Triethanolamine 0.1

Preservatives, trace pigments, trace fragrances, trace amount of purified water

Total 100.0

2. Nutritional Cosmetics (Content: Weight%)

Propofenone 0.01

Beeswax 4.0

Polysorbate 60 1.5

Sorbitan Sesquioleate 0.5

Liquid Paraffin 5.0

Squalane 5.0

Caprylic / Capric Triglycerides 5.0

Glycerin 3.0

Butylene Glycol 3.0

Propylene Glycol 3.0

Carboxy Vinyl Polymer 0.1

Triethanolamine 0.2

Preservatives, trace pigments, trace fragrances, trace amount of purified water

Total 100.0

3. Nutrition Cream (Content: Weight%)

Propafenone 0.005

Beeswax 10.0

Polysorbate 60 1.5

Sorbitan Sesquioleate 0.5

Liquid Paraffin 10.0

Squalane 5.0

Caprylic / Capric Triglycerides 5.0

Glycerin 5.0

Butylene Glycol 3.0

Propylene Glycol 3.0

Triethanolamine 0.2

Preservatives, trace pigments, trace fragrances, trace amount of purified water

Total 100.0

4. Massage cream (content: wt%)

Propafenone 0.005

Beeswax 10.0

Polysorbate 60 1.5

Sorbitan Sesquioleate 0.8

Liquid Paraffin 40.0

Squalane 5.0

Caprylic / Capric Triglycerides 4.0

Glycerin 5.0

Butylene Glycol 3.0

Propylene Glycol 3.0

Triethanolamine 0.2

Preservatives, trace pigments, trace fragrances, trace amount of purified water

Total 100.0

5. Pack (Content: Weight%)

Propafenone 0.005

Polyvinyl Alcohol 13.0

Sodium Carboxymethylcellulose 0.2

Allantoin 0.1

Ethanol 5.0

Nonylphenyl Ether 0.3

Preservatives, trace pigments, trace fragrances, trace amount of purified water

Total 100.0

Formulation example  2  : Pharmaceutical Formulations

1. Preparation of powder

2 g propaphenone

1g lactose

The above components were mixed and packed in airtight bags to prepare powders.

2. Preparation of Tablets

Propafenone 100mg

Corn Starch 100mg

Lactose 100mg

2 mg magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

3. Preparation of Capsule

Propafenone 100mg

Corn Starch 100mg

Lactose 100mg

2 mg magnesium stearate

After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

Figure 1: Effect of reducing melanin synthesis by propapenone in B16 melanoma cells (PFN: propafenone Hydrochloride)

Figure 2: Effect of reducing melanin synthesis by propapenone in human melanocytes (PFlan: propafenone hydrochloride)

Claims (5)

Skin whitening composition comprising propaphenone as an active ingredient Cosmetic composition for skin whitening comprising the composition of claim 1. The group of claim 2 wherein the composition consists of a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation and spray A composition characterized by having a formulation selected from. A pharmaceutical composition for skin whitening comprising the composition of claim 1 The composition according to any one of claims 1 to 4, wherein the propaphenone comprises 0.001 to 10% by weight relative to the total weight of the total composition.

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