KR20130055114A - C-kit inhibitor containing carnosic acid or derivatives of carnosic acid - Google Patents

Abstract

PURPOSE: Carnosic acid, a derivative thereof, or a pharmaceutically acceptable salt thereof is provided to suppress c-kit activation and signal transduction in melanocytes, and to improve skin whitening. CONSTITUTION: A c-kit activity inhibitor contains carnosic acid of chemical formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. The derivative is carnosic acid methyl ester or carnosic acid ethyl alcohol. The carnosic acid, a derivative thereof, or a pharmaceutically acceptable salt thereof is derived from rosemary and/or sage. The inhibitor contains 0.0001-10 wt% of the active ingredient. A composition for skin whitening contains the derivative of chemical formula 1 or a pharmaceutically acceptable salt thereof. The composition further contains one or more selected from a group consisting of a Gycyrrhiza extract, arbutin, ascorbic acid, and kojic acid.

Description

C-KIT INHIBITOR CONTAINING CARNOSIC ACID OR DERIVATIVES OF CARNOSIC ACID}

The present invention relates to a C-kit activity inhibitor.

As the number of people enjoying outside activities increases due to the increase in the leisure population, melanin pigmentation due to ultraviolet rays is intensified, and hyperpigmentation is a serious mental burden in terms of skin beauty, which can interfere with normal social activities. In particular, women in the Asian region have long favored white and fine skin, and this has been an important criterion of beauty, and the desire for prevention and improvement of abnormal skin pigmentation and hyperpigmentation has been increasing, which prevents excessive production of melanin. The development of cosmetics and drugs for whitening for the purpose is actively progressing. Therefore, the research on melanin is conducted for the purpose of preventing and treating skin cancer as well as satisfying the beauty desire for clean and white skin.

Until now, the development of whitening agents has been focused on inhibiting tyrosinase. Typical inhibitors of tyrosinase activity include kojic acid and arbutin, and antioxidants capable of reducing the melanin produced are tocopherol and vitamin-C. (L-Ascorbic acid) and derivatives thereof, but these whitening ingredients have poor stability in the prescription system, so they are degraded and colored, or their use is limited due to the occurrence of off-flavor, efficacy at the biological level, unclear effect and safety issues. It's happening. In addition, the effect is temporary and does not comprehensively care for skin health, which does not satisfy the needs of customers who want a fundamental whitening effect.

C-kit belongs to class III of receptor tyrosine kinase (RTK) and is known to be involved in the survival, proliferation and differentiation of melanocytes as one of the receptors on the cell surface of melanocytes. The ligand of the C-kit receptor is a stem cell factor (hereinafter referred to as 'SCF'). When SCF acts on the receptor, the SCF / C-kit interaction results in dimerization of the C-kit protein. It has the activity of phosphorylating itself. The intracellular signal transduction process induces Ras-Raf-MAP kinase activation and finally phosphorylates the microphthalmia-associated transcription factor (MITF), a helix-loop-helix and leucine zipper protein. By activating through to activate the transcription of melanogenesis enzymes such as tyrosinase (tyrosinase), TRP-2 and the like to induce melanin production in melanocytes.

SCF / C-kit signal transduction plays an important role in the signal transduction process that promotes melanin synthesis by UV light. Upon UV irradiation, SCF secreted by keratinocytes binds and interacts with C-kit to promote the differentiation of precursor melanocytes present in melanocytes into mature melanocytes and the transcription of enzymes involved in melanin synthesis. Thereby promoting the synthesis of melanin pigments.

Accordingly, the present inventors have tried to develop a new effective material that can overcome the disadvantages of the safety and whitening effect of the existing whitening material, the treatment of carnosic acid and its derivatives inhibits the activity of c-Kit whitening effect It was confirmed that bringing to complete the present invention.

Republic of Korea Patent Publication No. 10-2005-0071605

It is an object of the present invention to provide a C-kit inhibitor that reduces melanogenesis.

In order to achieve the above object, the present invention provides a C-kit activity inhibitor comprising carnoic acid represented by the following formula (1), its derivatives or pharmaceutically acceptable salts thereof as an active ingredient.

[Formula 1]

In Formula 1, R is -COOR ₁ , -CH ₂ OR ₁ , or -R ₂ OH, R ₁ is H or C ₁ -C ₆ alkyl group, R ₂ is a C ₁ -C ₆ alkyl group.

In addition, the present invention provides a composition for skin whitening comprising a carnosic acid derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. In the composition for skin whitening, R is -COOR ₃ , -CH ₂ OR ₃ , or -R ₃ OH, and R ₃ is a C ₁ -C ₆ alkyl group.

Carnosic acid, carnosic acid derivatives or pharmaceutically acceptable salts thereof of the present invention are useful because they can inhibit the activity of C-kit. By inhibiting the activity of C-kit, many biological responses mediated by C-kit can be suppressed. Carnosic acid derivatives or pharmaceutically acceptable salts thereof, on the other hand, can inhibit melanin production by inhibiting signal transduction of cells in melanocytes, thereby improving skin whitening. In particular, the present invention inhibits the activity of C-kit, inhibits pigmentation and brings about a blemish-improving effect, and is excellent in terms of skin safety because there is no side effect.

The present invention relates to a C-kit activity inhibitor comprising carnoic acid, a derivative thereof or a pharmaceutically acceptable salt thereof represented by Formula 1 as an active ingredient,

In Formula 1, R is -COOR ₁ , -CH ₂ OR ₁ , or -R ₂ OH, R ₁ is H or C ₁ -C ₆ alkyl group, R ₂ is a C ₁ -C ₆ alkyl group.

As used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group and includes straight or branched chains.

Carnosic acid herein is the formula (2).

As used herein, "pharmaceutically acceptable" means the approval of a government or equivalent regulatory body to use in animals, more specifically in humans, by avoiding significant toxic effects when used in conventional medicinal dosages. It can be received or approved, or listed in a pharmacopoeia or recognized as another general pharmacopeia.

As used herein, "pharmaceutically acceptable salt" means a salt according to one aspect of the present invention which is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. The salt is formed from (1) an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like; (3-hydroxybenzoyl) benzoic acid, or an acetic acid, propionic acid, hexanoic acid, cyclopentenepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2- 4-methylbicyclo [2,2,2] -oct-2-en-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert Acid addition salts formed with organic acids such as butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid; Or (2) salts formed when the acidic proton present in the parent compound is substituted.

As used herein, the term " active ingredient "alone refers to an ingredient that exhibits the desired activity or that can exhibit activity with a carrier that is not itself active.

The "C-kit activity inhibitor" of the present invention may be expressed as a "C-kit receptor antagonist", and stem cell factor (Stem cell factor (SCF)) as a ligand to the C-kit and subsequent neurotransmission mechanisms progress Means a material that interferes with the mechanism.

In a C-kit activity inhibitor of one aspect of the present invention, R ₁ is C ₁ -C ₃ alkyl and R ₂ is C ₁ -C ₃ It may be an alkyl group.

In addition, in the C-kit activity inhibitor of one aspect of the present invention, R ₁ is H or a methyl group and R ₂ may be a methyl group, specifically the carnosic acid derivative is carnosic acid methyl ester (Chemical Formula 3) or carno Methyl alcohol (Chemical Formula 4), but is not limited thereto.

In one C-kit activity inhibitor of the present invention, the carnosic acid, its derivatives or pharmaceutically acceptable salts thereof are rosemary ( Rosmarinus officinalis ) or sage ( Salvia officinalis ) derived from one or more plants selected from, can be obtained by extraction and purification by conventional extraction methods in the art. In another aspect of the invention, carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof include hydrothermal or solvent extracts of rosemary or sage. The solvent includes at least one organic solvent, in particular one selected from the group consisting of alcohol, hexane, acetone, ethyl acetate, diethyl ether, ethyl methyl ketone, and chloroform, and more specifically includes C ₁ to C ₅ alcohols. . In addition, in one aspect of the present invention, carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof may be obtained by synthesis by conventional methods in the art.

In the C-kit activity inhibitor, which is an aspect of the present invention, the active ingredient is preferably contained in an amount of 0.0001 to 10% by weight based on the total weight of the inhibitor, but in a range in which c-Kit activity is inhibited and no toxicity appears. It may be used above or below the above range depending on the intended use. When the active ingredient is contained less than 0.0001% by weight, a slight C-kit activity inhibitory effect is observed slightly, when contained in more than 10% by weight, it was confirmed that the toxicity appears. In view of the above, the active ingredient of the present invention may be contained in 0.0005 to 8% by weight, 0.001 to 6% by weight or 0.01 to 4% by weight.

C-kit activity inhibitor of one aspect of the present invention can be used as a composition for the prevention or treatment of skin pigment disorders. The skin pigment abnormality disease may include a disease in which melanin is inherently or acquiredly lacking, and in particular, may include skin hypopigmentation, hyperpigmentation or lack of pigmentation, and more specifically, atopic skin, psoriasis, blemishes, moles, blemishes or surpluses. It may include, but is not limited to, blotch. In addition, the C-kit activity inhibitor of one aspect of the present invention can be used as a pharmaceutical composition.

The present invention relates to a skin whitening composition comprising carnoic acid derivatives or pharmaceutically acceptable salts thereof represented by Formula 1 as an active ingredient in another aspect, wherein in Formula 1, R is -COOR ₃ , -CH ₂ OR ₃ , or —R ₃ OH and R ₃ is a C ₁ -C ₆ alkyl group.

In the present specification, "skin whitening" is understood as a result of the inhibition of the production of melanin, specifically, means the prevention, delayed expression or treatment of symptoms caused by melanin production, such as blemishes, freckles, skin aging, etc. .

In the composition for skin whitening which is an aspect of the present invention, R ₃ may be a C ₁ -C ₃ alkyl group.

In addition, in the composition for skin whitening, which is an aspect of the present invention, R ₃ may be a methyl group, and specifically, may include carnoic acid methyl ester or carnosic methyl alcohol, but is not limited thereto.

In a composition for skin whitening which is an aspect of the present invention, the carnosic acid derivative or pharmaceutically acceptable salt thereof is rosemary ( Rosmarinus officinalis ) or sage ( Salvia officinalis ) derived from one or more plants selected from, can be obtained by extraction and purification by conventional extraction methods in the art. In another aspect of the invention, the carnosic acid derivatives or their pharmaceutically acceptable salts include hydrothermal or solvent extracts of rosemary or sage. The solvent includes at least one organic solvent, in particular one selected from the group consisting of alcohol, hexane, acetone, ethyl acetate, diethyl ether, ethyl methyl ketone, and chloroform, and more specifically includes C ₁ to C ₅ alcohols. . In addition, in one aspect of the present invention, carnosic acid, derivatives thereof or pharmaceutically acceptable salts thereof may be obtained by synthesis by conventional methods in the art.

In a composition for skin whitening, which is an aspect of the present invention, the composition may further include one or more substances selected from the group consisting of ascorbyl glucoside, licorice extract, arbutin, ascorbic acid, and kojic acid.

In the composition for skin whitening which is an aspect of the present invention, the substance may be contained in 0.0001 to 10% by weight based on the total weight of the composition. If the substance is contained in less than 0.0001% by weight, it is difficult to show its efficacy by being absorbed by the skin, and when it is contained in an amount of more than 10% by weight, it is toxic to the skin or the skin stickiness is increased so that it is difficult to show its value as a cosmetic. Because. In view of the above, in the composition for skin whitening which is one aspect of the present invention, the substance may be contained in 0.001 to 9% by weight, 0.01 to 7% by weight or 0.5 to 5% by weight based on the total weight of the composition. .

The composition for skin whitening is not particularly limited in formulation, and may be appropriately selected as desired. For example, softening cream (skin lotion and milk lotion), nourishing cream, essence, nourishing cream, massage cream, pack, gel, essence, eye cream, eye essence, cleansing cream, cleansing foam, cleansing water, pack, powder, It may be prepared in any one or more formulations selected from the group consisting of body lotion, body cream, body oil and body essence, but is not limited thereto. In addition, the cosmetic composition for skin whitening may include using in the form of an external preparation for skin in the form of ointments, patches, and the like.

In addition, the composition for skin whitening may include a pharmaceutical composition, it may comprise a cosmetic composition.

The formulation of the pharmaceutical composition according to the present invention may be a solution, a suspension, a milk, a gel, a drip, a suppository, a patch or a spray, but is not limited thereto. The formulations can be readily prepared according to conventional methods in the art, and include excipients, hydrating agents, emulsifying accelerators, suspending agents, salts or buffers for controlling osmotic pressure, colorants, spices, stabilizers, preservatives, preservatives or other compatible agents. Adjuvants may be used as appropriate.

The effective ingredients of the pharmaceutical composition of the present invention will vary depending on the age, sex, weight, pathological condition and severity of the subject to be treated, administration route or judgment of the prescriber. Determination of the amount of application based on these factors is within the level of ordinary skill in the art and its daily dose is, for example, from 0.1 mg / kg / day to 100 mg / kg / day, more specifically from 5 mg / kg / day to 50 mg / / Day, but is not limited thereto.

The pharmaceutical composition of the present invention may be administered orally or transdermally, but is not limited thereto.

The cosmetic composition according to the present invention may be provided in all formulations suitable for topical application. For example, it may be provided as a solution, an emulsion obtained by dispersing an oil phase in an aqueous phase, an emulsion obtained by dispersing an oil phase in water, a suspension, a solid, a gel, a powder, a paste, a foam or an aerosol composition. Compositions of such formulations may be prepared according to conventional methods in the art.

The cosmetic composition according to the present invention may contain, in addition to the above-mentioned substances, other ingredients which can give a synergistic effect to the main effect, so long as they do not impair the main effect. In addition, the cosmetic composition according to the present invention may further include a moisturizer, an emulsifier, an ultraviolet absorber, a preservative, a fungicide, an antioxidant, a pH adjuster, organic and inorganic pigments, flavors, coolants, or limiting agents. The blending amount of the above components can be easily selected by those skilled in the art within the range that does not impair the object and effect of the present invention, the blending amount may be 0.01 to 5% by weight, specifically 0.01 to 3% by weight based on the total weight of the composition. have.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for illustrating the present invention and that the scope of the present invention is not construed as being limited by these embodiments.

Carnosic  purchase

Carnosic acid can be obtained from rosemary (Rosmarinus officinalis) or Sage (Salvia officinalis) by conventional extraction methods in the art. Specifically, the leaves of rosemary or sage are heated and extracted with 70% (v / v) to 100% (v / v) ethanol for 2 days in an extractor equipped with a reflux condenser at 50 ° C. Water is then added within a range of no more than 50% of the total volume of ethanol to induce precipitation formation including carnosic acid from the extract. At this time, the precipitation formation temperature is maintained not to exceed 20 ℃. Three times or more in the same manner as described above to induce the formation of precipitates with ethanol and water to obtain carnosic acid.

Carnos acid Methyl ester  Produce

1 g of carnosic acid obtained in Example 1 is dissolved in 30 ml of a mixed solvent of benzene and chloroform, and then 1.5 ml of TMS-diazomethane is slowly added dropwise. After the reaction temperature is maintained at 0 ℃ stirred for 30 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and then purified by column chromatography (hexane: ethyl acetate = 7: 1) to obtain 680 mg of carnoic acid methyl ester. NMR data of the carnoic acid methyl ester obtained by the above method is as follows.

¹ H NMR (300 MHz, CDCl ₃ ) 7.47 (s, 1H), 6.54 (s, 1H), 5.78 (s, 1H), 3.7 (s, 3H), 3.31 (1H, dt), 3.20 (1H, m ), 2.82-2.70 (2H, m), 2.29 (1H, m), 1.86 (m, 1H), 1.68 (m, 1H), 1.61 (m, 1H), 1.56 (dd, 1H), 1.46 (dt, 1H), 1.31 (m, 1H), 1.24 (m, 1H), 1.22 (d, 3H), 1.20 (d, 3H), 1.00 (s, 3H), 0.80 (s, 3H).

Carnos acid  Preparation of Methyl Alcohol

100 mg of carnoic acid obtained in Example 1 was dissolved in 5 ml of THF solvent, and 1.5 ml of LAH was slowly added dropwise. Then, the reaction temperature is maintained at 80 ℃ and stirred for 5 hours. After the reaction, the mixture was extracted with 5% aqueous hydrochloric acid solution and ethyl acetate, concentrated under reduced pressure, and then purified and separated by column chromatography (hexane: ethyl acetate = 10: 1) to give 32 mg of methyl carnosate methyl alcohol. The NMR data of carnoic acid methyl alcohol obtained by this method is as follows.

¹ H NMR (300 MHz, CDCl ₃ ) ¹ H NMR (300 MHz, CDCl ₃ ) 8.6 (s, 1H), 6.53 (s, 1H), 4.51 (d, 1H), 3.98 (d, 1H), 3.21 ( m, 2H), 2.86 (m, 2H), 1.86 (m, 1H), 1.68 (m, 1H), 1.61 (m, 1H), 1.56 (dd, 1H), 1.46 (dt, 1H), 1.31 (m) , 1H), 1.24 (m, 1H), 1.22 (d, 3H), 1.20 (d, 3H), 1.00 (s, 3H), 0.80 (s, 3H).

C- kit  Activity inhibition measurement

In order to determine whether the substance of Formula 2-4 has a C-kit activity inhibitory effect, RTK (receptor tyrosine kinase) efficacy search was performed. Each carnosic acid and carnosic acid derivative compound were made to have a final concentration of 1 μM and 10 μM, and RTK C-kit 5 ng and ATP 100 μM (final concentration) were added to each well of a 384 well plate for 1 minute at room temperature. Have a secondary reaction. As substrate, 5 nM (final concentration) of biotinylated poly [glutamine: tyrosine = 4: 1] was added to proceed with the secondary enzymatic reaction. Capture buffer including streptavidin-coated donor beads capable of binding to phosphorylated peptide substrates and receptor beads bound to antibodies (P-Tyr-100) ) To the third reaction. The degree of phosphorylation of the substrate is a microplate Fusion (Fusion ^TM This is determined by measuring the alpha screen signal using a microplate analyzer. In addition, the inhibitory effect was compared using Tyrphostin A51, which was previously known as a c-Kit activity inhibitor.

C-Kit activity inhibition experiment was repeated three times for each sample. DMSO was added to the positive control instead of the sample, DMSO was added to the negative control and the buffer was added to the enzyme to obtain the c-Kit inhibition rate. The c-Kit activity inhibition rate from the sensed signal was calculated by the following equation and the results are summarized in Table 1.

Test substance Test concentration (μM) Inhibition rate (%) Tyrphostin a51 10 75 Formula 2
(Carnosic acid) One 71 10 90 (3)
(Carnosic acid methyl ester) One 54 10 78 Formula 4
(Methyl alcohol of carnosate) One 60 10 85

As can be seen in Table 1, carnoic acid and carnosic acid derivatives of Formulas 2 to 4 were found to have superior c-Kit inhibition at lower concentrations compared to Tyrphostin A51, which is known as an inhibitor of c-Kit activity.

Pigmentation Inhibitory Effect Experiment

In order to verify the skin whitening effect of carnosic acid and carnosic acid derivatives according to the present invention, a pigmentation inhibitory effect experiment was conducted as follows. The aforementioned carnosic acid derivatives were evaluated using the compositions formulated with the ingredients and amounts listed in Table 2 below.

Twelve healthy men were attached with an opaque tape with six 1.5cm diameter holes in the upper forearm of the subject, and 1.5 ~ 2 times the UVB of the minimum Erythema Dose of each subject. Induced blackening of the skin by injecting, each of the Examples 1 to 3 in each morning and evening were corrected twice daily, two months later was measured using a color difference meter

Component (% by weight) Experimental Example 1 Experimental Example 2 Experimental Example 3 Comparative Experimental Example 1 Comparative Experiment 2 Kojic acid - - - - 1.0 2. Formula 2
(Carnosic acid) 1.0 - - - - 3. Formula 3
(Carnosic acid methyl ester) - 1.0 - - - 4. Formula 4
(Methyl alcohol of carnosate) - - 1.0 - -        5. Purified water To 100 To 100 To 100 To 100 To 100 6. Dipropylene Glycol 5.0 5.0 5.0 5.0 5.0 7. Butylene Glycol 5.0 5.0 5.0 5.0 5.0 8. Bio Sacrite Gum-1 4.0 4.0 4.0 4.0 4.0 9. Test substance
1.0 1.0 1.0 1.0 1.0 10. Ethanol 5.0 5.0 5.0 5.0 5.0 11.Phenyl Trimethicone 0.2 0.2 0.2 0.2 0.2 12. Polyoxyethylene Hydrogenated Castor Oil 0.5 0.5 0.5 0.5 0.5 13. Preservatives Suitable amount Suitable amount Suitable amount Suitable amount Suitable amount 14. Incense Suitable amount Suitable amount Suitable amount Suitable amount Suitable amount

The effect was judged by measuring the degree of blackness of the skin using a color difference meter (Minolta CR2002). L, a, b colorimeters are used to display the color. In the present invention, the "L" value representing the contrast of the skin was obtained and analyzed (the unburned Korean skin color generally shows a value of 50 to 70). The L value was calibrated with a standard whiteboard and the measurements were measured evenly by repeating the measurement at least 5 times in one site.

When the test substance is applied, the L value is gradually increased when the effect is applied, and the comparison between the test substances is calculated according to the following equation (2) of the difference in skin color (ΔL) at the start and the end of the application. The results are shown in Table 3.

Test substance Whitening effect (△ L) Comparative Experimental Example 1 0.5 Comparative Experimental Example 2 1.80 Experimental Example 1 2.42 Experimental Example 2 2.04 Experimental Example 3 1.98

As can be seen in Table 3, the carnoic acid and its derivative-containing composition of Experimental Example 1-3 shows a superior whitening effect than Comparative Experimental Example 1 containing no carnoic acid and its derivatives and Comparative Example 2 containing kojic acid. No adverse effects were observed in the skin.

Blemish improvement effect experiment

Ten healthy women with blemishes were selected and applied to Experimental spots 1-3 for 3 weeks twice a day on the blemish area of the face.

After the experiment was completed, the degree of pigment adherence by experts was visually determined, and the degree of improvement of blemishes was judged by subjective judgment of the test subjects, and evaluated whether or not the improvement of blemishes of Experimental Example 1 was effective and no effect. The results are shown in Table 4.

Effective (persons) No difference (persons) Expert judgment 7 3 Subjective Judgment 8 2

As can be seen from the results of Table 4, Experimental Example 1 containing carnosic acid showed a blemish-improving effect for at least seven of 10 subjects.

Skin stability assessment

In order to evaluate the safety of the whitening cosmetic composition according to the present invention on the skin, the degree of irritation to the skin of carnosic acid and carnosic acid derivatives was measured.

Thirty-nine healthy adult women and one male with an average age of 37.3 years were subjected to a closed closure patch of the formulation formulated on the back as prescribed in Table 3 for 24 hours and visually read the skin reaction for 30 minutes and 24 hours after removal. It was. The criteria for skin irritation were referred to CTFA guidelines (1981) and Frosch & Kligman's criteria. Reaction test readings are shown in Table 5 below.

reaction weight Criteria for judgment - 0.0 No reaction + 1.0 Faint erythema ++ 2.0 The border is clear but weak erythema, edema and palsy +++ 3.0 Pronounced erythema, papules and blisters ++++ 4.0 Cannon

It was confirmed that the numerical score of the skin average reactivity was 0 in all 40 patients who were subjected to Experimental Examples 1 to 3 of the present invention, so that no skin irritation was induced. In particular, since the skin average response score is determined to be very safe to 1 or less, the present invention was confirmed that the skin safety is very excellent.

Hereinafter, the formulation examples of the composition according to the present invention, but the pharmaceutical composition and cosmetic composition is applicable to a variety of formulations, which is intended to explain in detail only, not intended to limit the present invention.

[Formulation Example 1] Softening lotion (skin lotion)

According to the composition described in Table 6 below to prepare a flexible longevity in a conventional manner.

Compounding ingredient Content (% by weight) Active ingredient containing at least one selected from the group consisting of carnosic acid and carnosic acid derivatives 0.1 glycerin 3.0 Butylene glycol 2.0 Propylene glycol 2.0 Carboxyvinyl polymer 0.1 Phage-12 nonylphenyl ether 0.2 Polysorbate 80 0.4 ethanol 10.0 Triethanolamine 0.1 Preservative, coloring, fragrance Suitable amount Purified water Balance

[Formulation Example 2] Nutritional lotion (Milk lotion)

Nutritional longevity was prepared in a conventional manner according to the composition shown in Table 7.

Compounding ingredient Content (% by weight) Active ingredient containing at least one selected from the group consisting of carnosic acid and carnosic acid derivatives 0.1 glycerin 3.0 Butylene glycol 3.0 Propylene glycol 3.0 Carboxyvinyl polymer 0.1 Wax 4.0 Polysorbate 60 1.5 Caprylic / capric triglyceride 5.0 Squalane 5.0 Sorbitacecequioleate 1.5 Liquid paraffin 0.5 Cetearyl alcohol 1.0 Triethanolamine 0.2 Preservative, coloring, fragrance Suitable amount Purified water Balance

[Formulation Example 3] Nourishing cream

Nutritional cream was prepared in a conventional manner according to the composition shown in Table 8.

Compounding ingredient Content (% by weight) Active ingredient containing at least one selected from the group consisting of carnosic acid and carnosic acid derivatives 0.1 glycerin 3.0 Butylene glycol 3.0 Liquid paraffin 7.0 Beta Glucan 7.0 Carbomer 0.1 Caprylic / capric triglyceride 3.0 Squalane 5.0 Cetearyl glucoside 1.5 Sorbitan stearate 0.4 Polysorbate 60 1.2 Triethanolamine 0.1 Preservative, coloring, fragrance Suitable amount Purified water Balance

[Formulation Example 4] Massage cream

To prepare a massage cream in a conventional manner according to the composition shown in Table 9.

Compounding ingredient Content (% by weight) Active ingredient containing at least one selected from the group consisting of carnosic acid and carnosic acid derivatives 0.1 glycerin 8.0 Butylene glycol 4.0 Liquid paraffin 45.0 Beta Glucan 7.0 Carbomer 0.1 Caprylic / capric triglyceride 3.0 Wax 4.0 Cetearyl glucoside 1.5 Sesquioleic acid sorbitan 0.9 Vaseline 3.0 paraffin 1.5 Preservative, coloring, fragrance Suitable amount Purified water Balance

[Formulation Example 5] Pack

To prepare a pack in a conventional manner according to the composition described in Table 10 below.

Compounding ingredient Content (% by weight) Active ingredient containing at least one selected from the group consisting of carnosic acid and carnosic acid derivatives 0.1 glycerin 4.0 Polyvinyl alcohol 15.0 Hyaluronic acid extract 5.0 Beta Glucan 7.0 Allantoin 0.1 Nonyl phenyl ether 0.4 Polysorbate 60 1.2 Ethanol preservative 6.0 Good Preservative, coloring, fragrance Suitable amount Purified water Balance

[Formulation Example 6] ointment

The ointment was prepared in a conventional manner according to the composition described in Table 11.

Compounding ingredient Content (% by weight) Active ingredient containing at least one selected from the group consisting of carnosic acid and carnosic acid derivatives 0.1 glycerin 8.0 Butylene glycol 4.0 Liquid paraffin 15.0 Beta Glucan 7.0 Carbomer 0.1 Caprylic / capric triglyceride 3.0 Squalane 1.0 Cetearyl glucoside 1.5 Sorbitan stearate 0.4 Cetearyl alcohol 1.0 Wax 4.0 Preservative, coloring, fragrance Suitable amount Purified water Balance

While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. something to do. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (13)

C-kit activity inhibitor comprising carnoic acid represented by the following formula (1), its derivatives or pharmaceutically acceptable salts thereof as an active ingredient.
[Formula 1]

In Formula 1, R is -COOR ₁ , -CH ₂ OR ₁ , or -R ₂ OH, R ₁ is H or C ₁ -C ₆ alkyl group, R ₂ is a C ₁ -C ₆ alkyl group. The method of claim 1,
R ₁ is C ₁ -C ₃ alkyl and R ₂ is C ₁ -C ₃ C-kit activity inhibitor which is an alkyl group. The method of claim 1,
R ₁ is H or a methyl group and R ₂ is a methyl group, C-kit activity inhibitor. The method of claim 1,
The carnosic acid derivative is carnosic acid methyl ester or carnosic acid methyl alcohol, C-kit activity inhibitor. The method of claim 1,
Carnosic acid, its derivatives, or a pharmaceutically acceptable salt thereof, is derived from one or more plants selected from rosemary or sage. The method of claim 1,
The active ingredient is contained in 0.0001 to 10% by weight based on the total weight of the inhibitor, C-kit activity inhibitor. Carnosic acid derivatives represented by the following formula (1) or pharmaceutically acceptable salts thereof comprising a composition for skin whitening as an active ingredient.
[Formula 1]

In Chemical Formula 1, R is —COOR ₃ , —CH ₂ OR ₃ , or —R ₃ OH, and R ₃ is a C ₁ -C ₆ alkyl group. The method of claim 7, wherein
R ₃ is a C ₁ -C ₃ alkyl group, the composition for skin whitening. The method of claim 7, wherein
R ₃ is a methyl group, the composition for skin whitening. The method of claim 7, wherein
The carnosic acid derivative is carnosic acid methyl ester or carnosic acid methyl alcohol, the composition for skin whitening. The method of claim 7, wherein
The carnosic acid derivative or pharmaceutically acceptable salt thereof is derived from one or more plants selected from rosemary or sage, the composition for skin whitening. The composition of claim 7, wherein the composition further comprises one or more substances selected from the group consisting of ascorbyl glucoside, licorice extract, arbutin, ascorbic acid, and kojic acid. The composition for skin whitening according to claim 12, wherein the substance is contained in an amount of 0.0001 to 10% by weight based on the total weight of the composition.