KR101452061B1 - Agents for skin whitening containing artemisinic acid, its derivatives and pharmaceutically acceptable salts thereof - Google Patents

Abstract

The present invention relates to a skin whitening composition, which comprises an artemisinic acid and a derivative thereof as an active ingredient. The composition comprising atemic acid and its derivatives not only can be used safely without side effects on the skin but also inhibits melanin formation and is excellent in inhibition of pigment deposition. Therefore, a composition containing these compounds as an active ingredient can be used for improvement of spots, .

Description

TECHNICAL FIELD [0001] The present invention relates to a skin whitening agent containing atemic acid, a derivative thereof, and a pharmaceutically acceptable salt thereof,

The present invention relates to a composition for skin whitening, and more particularly, to a composition for skin whitening which is excellent in product stability and can be safely used without adverse effects on the skin, and which is excellent in inhibiting melanin formation, The present invention relates to a composition for skin whitening comprising an acceptable salt.

The skin color of a person is determined by the concentration and distribution of melanin in the skin. Such melanin concentration and distribution are affected not only by genetic factors but also by environmental or physiological conditions such as sun UV, fatigue, and stress. The melanin pigment, which is produced in melanocytes of human skin, is a phenolic high molecular substance having a complex form of black pigment and protein and plays an important role in blocking skin damage caused by ultraviolet rays. It has been reported that the action of tyrosinase in melanocytes is most important for melanin biosynthesis. Tyrosinase plays a key role in the skin blackening process by converting tyrosine, an amino acid, into dopa (DOPA) and dopaquinone, the intermediate products of melanin polymer production. However, the pathway through which melanin is made is known, but the mechanism by which melanin synthesis, a previous step in which tyrosinase acts, is not yet elucidated.

When such a synthesis of melanin occurs excessively in the skin, it darkens skin tone, and causes spots and freckles. Thus, inhibiting the synthesis of melanin pigment in the skin can brighten skin tone to achieve whitening of the skin, and can improve skin hypercholesterolemia caused by ultraviolet rays, hormones and genetic causes, such as spots and freckles have.

Therefore, in the past, substances having inhibitory activity against tyrosinase such as hydroquinone, ascorbic acid, kojic acid, glutathione, etc. have been used and skin whitening and skin hyperpigmentation Improvement. However, although hydroquinone exerts a predetermined whitening effect, it has a problem that skin irritation is serious and the compounding amount should be limited to a very small amount. Ascorbic acid is easily oxidized, so that the cosmetic composition containing the hydroquinone is discolored and deteriorated, Koji acid is insufficient in the solution, and the manufacturing process of the cosmetic is complicated. Furthermore, thiol compounds such as glutathione and cysteine have not only unpleasant odors but also problems with transdermal absorption, and their glycosides and derivatives are also highly polar, making them difficult to use as a blending ingredient for cosmetics. In addition, vitamin C is easily oxidized in an aqueous solution state and can not produce a sustained effect. Accordingly, recently, compositions for whitening skin including natural herbal medicine extracts have been developed. However, since most of them are colored, there is a problem in compounding, and since the effective ingredient is not identified, the same effect can not be expected when manufacturing a product.

On the other hand, artemisinic aicd and its derivatives dihydroartemisinic acid are known as Artemisia It is a precursor of Artemisinin, a representative antimalarial drug derived from annua L , and may be isolated from mugwort or produced by microbial culture. Atemic acid and dihydroatomic acid have been actively studied for their role as precursors in the production of atemicinin, and antifungal activity and anticancer efficacy have been reported (Galal AM et al . , J Nat Prod , 68 (6), 2005; Sun WC et . al . Zhongguo Yao Li Xue Bao. 13 (6), 1992). However, the whitening effect of these substances has not been reported.

Accordingly, the present inventors have made intensive efforts to develop a single substance having excellent whitening effect, high stability, and no skin side effect in order to solve the problems as described above.

It is an object of the present invention to provide a skin whitening composition comprising atemic acid, a derivative thereof, and a pharmaceutically acceptable salt thereof.

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

It is another object of the present invention to provide a pharmaceutical composition for skin whitening comprising the composition.

In one aspect, the invention is directed to a composition for skin whitening comprising artemisinic acid, derivatives thereof, and pharmaceutically acceptable salts thereof.

The artemisinic acid of the present invention is an artemisinin derivative. The IUPAC name is 2 - [(4R) -4,7-dimethyl-1,2,3,4,4a, 5,6,8a- octahydronaphthalen-1-yl] prop-2-enoic acid. Its derivative dihydroartemisinic acid has the structure of formula (2).

The athemic acid and its derivative dihydroatheximinic acid of the above formulas 1 and 2 can be prepared according to a known preparation method for them, for example, Artemisia annua L , or obtained from a microorganism culture such as Saccharomyces cerevisiae or chemically synthesized (for example, artemic acid from Sami Labs Limited).

In order to examine the whitening effect of the athemic acid and derivatives thereof of the present invention, it was found that the intracellular tyrosinase activity generally used for whitening substance screening as compared with the vitamin C (vitamin C) And melanin production inhibitory activity, the atemic acid of the present invention and its derivative dihydroatomic acid were superior to vitamin C by about 50% in inhibiting melanin formation activity at the same concentration. Therefore, the athemic acid and its derivative dihydroatomic acid of the present invention is excellent in whitening effect due to inhibition of melanin production.

The athemic acid of Formula 1 and the dihydroatomic acid of Formula 2 of the present invention may be used in the form of a pharmaceutically acceptable salt. Examples of such salts include pharmacologically acceptable acid groups formed by free acids, There is a metal salt formed by a salt or base. Examples of the inorganic acid include hydrochloric acid, sulfuric acid, bromic acid, sulfurous acid and phosphoric acid. Examples of the organic acid include citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid and methanesulfonic acid. But is not limited thereto. The metal salts include alkali metal salts or alkaline earth metal salts, and sodium, potassium or calcium salts are useful.

In the skin whitening composition of the present invention, the amount of atemic acid and derivatives thereof is preferably 0.001 to 10% by weight based on the total composition. When the content is less than 0.0001% by weight, the whitening effect is too weak. When the content is more than 15% by weight, the increase of the effect is not increased and the stability of the shape is not ensured. More preferably, the atemic acid and derivatives are included in an amount of 0.001 to 5% by weight based on the total composition.

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

The cosmetic composition contains, in addition to atemic acid as an active ingredient, components commonly used in cosmetic compositions, and may contain conventional auxiliary agents and / or carriers such as, for example, antioxidants, stabilizers, solubilizers, vitamins, . In addition, the cosmetic composition may further include a skin absorption promoting substance to improve the skin whitening effect.

The cosmetic composition of the present invention can be prepared into any of the formulations conventionally produced in the art and can be used as a solution, a suspension, an emulsion, a paste, a gel, a cream, a lotion, a powder, a soap, , Oil, powder foundation, emulsion foundation, wax foundation and spray, but is 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, a cream or a gel, an animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide .

In the case where 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 as a carrier component. Especially, in the case of a spray, a mixture of chlorofluorohydrocarbons, propane / Propane, < / RTI > 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.

In the case where the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tragacanth, and the like may be used.

When the formulation of the present invention is an interface-active agent-containing cleansing, the carrier component is selected from aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters.

In the cosmetic composition of the present invention, the amount of the atemic acid, its derivative and the pharmaceutically acceptable salt thereof may be 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 atemic acid, its derivative, and pharmaceutically acceptable salt thereof may be 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 conventionally used in the manufacture of pharmaceutical compositions. Examples of suitable carriers, diluents or excipients are as follows: starch, sugar, lactose, dextrin, mannitol, sorbitol, crystalline cellulose, low-boiling hydroxypropylcellulose, sodium carboxymethylcellulose, arabic gum, amylopectin, , And excipients such as synthetic aluminum silicates; Fillers and extenders such as calcium phosphate and silicic acid derivatives; But are not limited to, starch, sugar, mannitol, trehalose, dextrin, amylopectin, sucrose, gluten, arabic gum, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose Binders such as cellulose derivatives, gelatin, alginate, and polyvinylpyrrolidone; Lubricants such as talc, magnesium stearate or calcium, hydrogenated castor oil, talcum powder, and solid polyethylene glycols; Disintegrants such as povidone, sodium croscarmellose, and crospovidone; And surface active agents such as polysorbate, cetyl alcohol, and glycerol monostearate.

The pharmaceutical composition of the present invention may be administered orally or parenterally in the form of oral preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, external preparations such as ointments and creams, suppositories and sterilized injection solutions, May be formulated and used in any form suitable for the target formulation.

The pharmaceutical compositions according to the present invention can be administered to mammals such as rats, mice, livestock, humans, and the like in various routes such as parenteral, oral, and the like, all manner of administration can be expected, Rectal, or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections. At this time, transdermal administration is preferable for the parenteral route, and local application is most preferable.

The dosage of the formulation varies depending on the age, sex, weight, symptom, and method of administration of the subject, and in the case of an external preparation, it is preferably 1.0 to 3.0 per day, and is applied 1 to 5 times a day for 1 month or longer.

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

Meanwhile, in a specific example of the present invention, the skin cumulative stimulation test for atemic acid and derivatives thereof showed that atemic acid and its derivative dihydroatomic acid are natural substances and harmless to human body. Accordingly, since the athemic acid and derivatives thereof of the present invention have little toxicity and side effects, they can be safely used even in long-term use, and can be safely applied to cosmetic compositions and pharmaceutical compositions as described above.

According to the present invention, atemic acid, a derivative thereof and a pharmaceutically acceptable salt thereof have a higher inhibitory effect on melanin formation than vitamin C, which is a main component of conventional whitening agents. In addition, it was proved to be a safe substance in human use because no toxicity or irritation occurred in the human safety test. Accordingly, the atemic acid, derivatives thereof and pharmaceutically acceptable salts thereof of the present invention can be usefully used for cosmetics, medicines or foods for skin whitening.

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

Example  One : Atemic acid  ≪ RTI ID = 0.0 > B16 < / RTI & Melanoma  Measurement of melanin production inhibitory effect of cells

The inhibitory effect of atemic acid (Sami Labs Limited) and its derivative dihydroartemic acid (Xian Tian Ben Bio-Engineering) on melanin production inhibition was measured using rat blue pigment cells (B16 melanoma cells, ATCC) And inhibited the production of melanin by vitamin C.

This experiment murine melanoma (B-16 F10) and then inoculated with 10% of the cells in 6-well plate with DMEM medium containing FBS (fetal bovine serum) 1 × 10 5 pieces per well, 5% CO _2, and Cells were incubated at 37 ° C until approximately 80% of cells were attached to the well bottom. After the exchange of culture medium and process the sample to the medium at different concentrations, and cultured 3 days under 5% CO _2, 37 ℃. The concentrations of atemic acid and dihydroatomic acid were determined to be 1 uM, 5 uM, and 10 uM without cytotoxicity. Cells from which the medium was removed were washed with PBS (phosphatized buffer saline), and treated with trypsin to recover the cells. The recovered cells were counted using a hematocytometer, and the cell numbers of each treatment group were adjusted to the same number. Then, the cells were transferred to a 2-mL tube, centrifuged at 5,000 to 10,000 rpm for 10 minutes, and the supernatant was removed to obtain a pellet. The cell pellet was dried at 60 ° C, and 1M sodium hydroxide solution (100%) containing 10% DMSO was added thereto to obtain intracellular melanin in a 60 ° C thermostat. The amount of melanin per cell constant was determined by measuring the absorbance at 490 nm with a microplate reader (Powerwave X, Bio-tek INC, VT). The results are shown in Table 1 below.

sample Treatment concentration (uM) Melanin production inhibition rate (%) Vitamin C One 0 Vitamin C 5 5 Vitamin C 10 15 Atemic acid One 6 Atemic acid 5 63 Atemic acid 10 78 Dihydroartemic acid One 2 Dihydroartemic acid 5 59 Dihydroartemic acid 10 65

As shown in Table 1 above, atemicinic acid and its derivative dihydroatomic acid exhibited a better melanin production inhibitory rate than vitamin C at the same treatment concentration.

Example  2 : Atemic acid  And derivatives thereof Human melanin  Measurement of melanin production inhibitory effect of cells

Comparison of the inhibitory effect of athemic acid and its derivative dihydroatemic acid on the inhibition of melanin formation by human melanocytes and inhibition of intracellular tyrosinase activity by vitamin C, which is known to inhibit melanin production Respectively.

Human epidermal melanocytes (from neonatal) cells purchased from Cascade Biologics were also cultured in medium 254 medium containing Human Melanocyte Growth supplement purchased from the same company. Human epidermal melanocytes under a 6-well plate were inoculated to 1 × 10 ⁵ pieces per well 5% CO _2, 37 ℃ cells are incubated until at least about 80% adhesion to the well bottom. After the culture, the medium was changed, and the sample was treated with the medium at a concentration of 5% CO _{2 at} 37 ° C for 5 days while changing the medium once every two days. The concentration range of atemic acid and dihydroartemic acid was determined as 1 uM, 5 uM, and 10 uM without cytotoxicity. After the treatment, the medium was removed, washed with PBS (phosphatized buffer saline), and treated with trypsin to recover the cells. The recovered cells were counted using a hematocytometer, and the cells were homogenized in a 2-mL tube, centrifuged at 5,000 to 10,000 rpm for 10 minutes (Biofuge, Heraeus), and the supernatant was removed To obtain a pellet. The cell pellet was dried at 60 ° C, and 1M sodium hydroxide solution (100%) containing 10% DMSO was added thereto to obtain intracellular melanin in a 60 ° C thermostat. The amount of melanin per cell constant was determined by measuring the absorbance at 490 nm with a microplate reader. The results are shown in Table 2 below.

sample Treatment concentration (uM) Melanin production inhibition rate (%) Vitamin C One 0 Vitamin C 5 4 Vitamin C 10 18 Atemic acid One 12 Atemic acid 5 36 Atemic acid 10 54 Dihydroartemic acid One 2 Dihydroartemic acid 5 39 Dihydroartemic acid 10 55

As shown in Table 2 above, atemicinic acid and its derivative dihydroatheximinic acid showed better suppression rate of intracellular melanin production inhibitory rate than vitamin C at the same treatment concentration.

Example  3: Evaluation of whitening effect at animal level

The whitening effect of atemic acid and its derivatives was measured using brown guinea pigs (Brown guinea pigs), which are known to cause pigmentation by ultraviolet light similar to humans.

In order to induce pigmentation by ultraviolet rays (UV) in the brown guinea pig, a shading aluminum foil having a square window of 3 x 3 cm ² was adhered to the skin from which the hair of brown marmot arrangement was removed, and then SE lamp -320 nm, Toshiba) (total irradiation energy amount = 1350 mJ / cm ² ). After irradiating ultraviolet rays, the aluminum foil was peeled off and samples (atemic acid, dihydroatomic acid, and vitamin C) were applied in the following manner. Pigmentation was observed 2 or 3 days after ultraviolet irradiation, and reached the maximum after about 2 weeks, and each sample was applied from this point.

The number of times of application was once or twice a day for 50 days. The sample was dissolved and diluted using a specific solvent (Propylene Glycol: Ethanol: Water = 5: 3: 2), applied with a cotton swab, and the other part was coated with solvent. Cumulative irritation was also observed with the effect determination.

The results were determined by measuring the degree of blackness 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 is used as an index in the present invention. The L ^* value was corrected with a standard white plate, and the L ^* value was measured repeatedly at least once at one site and the pigmentation was made even. The difference in skin color (L ^* ) at the application start time and the completion time was determined, and the effect was judged by this value. The results are shown in Table 3 below.

(Empirical formula 1)

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

The L ^* value is obtained for the sample application site and the control site, and the effect of the whitening substance can be found by comparing.

sample Treatment concentration (%) The whitening effect (? L) Atemic acid 0.2 0.55 Atemic acid 1.0 0.64 Dihydroartemic acid 0.2 0.52 Dihydroartemic acid 1.0 0.62 Vitamin C 1.0 0.49 Control group 0.33

As shown in Table 3, atemic acid and its derivative dihydroaestemic acid showed better whitening effect than vitamin C, and no cumulative irritation was observed during the test for application of the test substance, thus showing excellent safety.

Example  4 : Atemic acid  And its derivatives in human skin

4-1. Preparation of external skin preparation containing atemic acid and derivatives thereof

In order to confirm that the atemic acid and its derivatives proved to be excellent in the whitening effect as described above are safe for human skin, a skin external preparation containing atemic acid, dihydroartemic acid and vitamin C is prepared and skin safety Verification experiments were performed.

Skin external preparations containing atemic acid, dihydroartemic acid, and vitamin C were prepared with the ingredients shown in Table 4 below. In Table 4, the control group is an external preparation for skin which does not contain a tyrosinase inhibitor. Test group 1 and test group 2 are each an external preparation for skin including atemic acid, dihydroartemic acid and vitamin C, respectively.

For the preparation of the external preparation for skin, purified water, glycerin, and butylene glycol were mixed and dissolved at 70 (water part), and the other components were dissolved at 70 (oil part) except for the above three components and trimethanolamine. The oil part was added to the water-based part, and the mixture was firstly emulsified by stirring with a homomixer (Tokushu Kika, Japan), and trimethanolamine was finally added thereto. After the bubbles generated in the mixed solution were removed, the mixture was cooled to room temperature to prepare an external preparation for skin.

ingredient content (%) Control group Test group 1 Test group 2 Test group 3 Purified water 72 72 72 72 glycerin 8.0 8.0 8.0 8.0 Butylene glycol 4.0 4.0 4.0 4.0 Atemic acid 0 1.0 0 0 Dihydroartemic acid 0 0 1.0 0 Vitamin C 0 0 0 1.0 Caprylic Capri
Triglyceride 8.0 8.0 8.0 8.0 Squalane 5.0 5.0 5.0 5.0 Cetearyl glucide 1.5 1.5 1.5 1.5 Sorbitan stearate 0.4 0.4 0.4 0.4 Cetearyl alcohol 1.0 1.0 1.0 1.0 Trimethanolamine 0.1 0.1 0.1 0.1 Gross weight 100 100 100 100

4-2. Skin Cumulative Stimulation Test

Using the skin external preparations prepared in Example 4-1, a total of 9 times 24-hour cumulative pellets were applied to 30 healthy adults on the upper forearm every other day to determine whether atemic acid stimulates the skin Were measured.

A pin chamber (Finn chamber, Epitest Ltd, Finland) was used as the deposition method. 15 [mu] l of each of the external preparations for skin was dropped into the chamber, followed by applying a patch. The degree of skin reaction on each occasion was scored using the following formula, and the results are shown in Table 5 below.

(Empirical formula 2)

Average response = [[Reaction index x response / total number of subjects x maximum score (4 points)] x 100] Number of tests (9 times)

At this time, ±, 1, 2, and ++ were given a score of ±, 1, and 4, respectively, and a safe composition was determined when the average degree of reaction was less than 3.

In Table 5, in test group 1, the numbers of persons corresponding to ±, +, and ++ were 1, 0, and 0, respectively. [((1x2) / (20x4)] x 100/9 = 0.13, and the average degree of reaction was 0.37, which was 3 or less.

As shown in Table 5 above, skin external preparations containing atemic acid (test group 1) and derivatives thereof dihydroatheximinic acid (test group 2) exhibited a distinct cumulative stimulation pattern as in the control group or external skin preparations including vitamin C And it was judged to be safe for human skin.

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

Formulation example  One  : Cosmetics  Formulation

1. Flexible life (content:% by weight)

Atemic acid 0.01

Glycerin 3.0

Butylene glycol 2.0

Propylene glycol 2.0

Carboxyvinyl polymer 0.1

Ethanol 10.0

Triethanolamine 0.1

Preservative, trace pigment, trace flavor, trace amount of purified water

Total 100.0

2. Nourishing lotion (content:% by weight)

Atemic acid 0.01

Beeswax 4.0

Polysorbate 60 1.5

Sorbitan sesquioleate 0.5

Liquid paraffin 5.0

Squalane 5.0

Caprylic / Capric Triglyceride 5.0

Glycerin 3.0

Butylene glycol 3.0

Propylene glycol 3.0

Carboxyvinyl polymer 0.1

Triethanolamine 0.2

Preservative, trace pigment, trace flavor, trace amount of purified water

Total 100.0

3. Nourishing cream (content:% by weight)

Atemic acid 0.005

Wax 10.0

Polysorbate 60 1.5

Sorbitan sesquioleate 0.5

Liquid paraffin 10.0

Squalane 5.0

Caprylic / Capric Triglyceride 5.0

Glycerin 5.0

Butylene glycol 3.0

Propylene glycol 3.0

Triethanolamine 0.2

Preservative, trace pigment, trace flavor, trace amount of purified water

Total 100.0

4. Massage cream (content:% by weight)

Atemic acid 0.005

Wax 10.0

Polysorbate 60 1.5

Sorbitan sesquioleate 0.8

Liquid paraffin 40.0

Squalane 5.0

Caprylic / Capric Triglyceride 4.0

Glycerin 5.0

Butylene glycol 3.0

Propylene glycol 3.0

Triethanolamine 0.2

Preservative, trace pigment, trace flavor, trace amount of purified water

Total 100.0

5. Pack (content:% by weight)

Atemic acid 0.005

Polyvinyl alcohol 13.0

Sodium carboxymethylcellulose 0.2

Allantoin 0.1

Ethanol 5.0

Nonyl phenyl ether 0.3

Preservative, trace pigment, trace flavor, trace amount of purified water

Total 100.0

Formulation example  2  : Pharmaceutical preparations

1. Manufacturing of powder

Atemic acid 2g

Lactose 1g

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

2. Preparation of tablets

Atemic acid 100 mg

Corn starch 100 mg

100mg of milk

Magnesium stearate 2 mg

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

3. Preparation of capsules

Atemic acid 100 mg

Corn starch 100 mg

100mg of milk

Magnesium stearate 2 mg

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

Claims (7)

A cosmetic composition for skin whitening comprising, as an active ingredient, atemic acid, dihydroartemic acid or a pharmaceutically acceptable salt thereof. delete The composition of claim 1, wherein the composition is a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation and spray ≪ / RTI > The composition according to claim 1, wherein the atemic acid, dihydroatomic acid or pharmaceutically acceptable salt thereof comprises 0.001 to 10% by weight based on the total composition. A pharmaceutical composition for skin whitening comprising, as an active ingredient, atemic acid, dihydroartemic acid or a pharmaceutically acceptable salt thereof. delete 6. A composition according to claim 5 wherein the atemic acid, dihydroatomic acid or pharmaceutically acceptable salt thereof comprises 0.001 to 10% by weight based on the total composition.