KR101386623B1 - A composition for skin-whitening comprising trimethylphytosphingosine - Google Patents

Abstract

The present invention provides a cosmetic composition for skin whitening and a pharmaceutical composition for preventing or treating pigmentation, including trimethyl phytosphingosine or cyclic trimethyl phytosphingosine, a pharmaceutically acceptable salt thereof, or a solvate thereof.
The composition according to the present invention is not only effective in the prevention or treatment of the whitening effect and pigmentation due to the melanin production inhibitory effect, but also can exhibit a more effective melanin production inhibitory effect by forming a complex composition with arbutin. In addition, the composition according to the present invention can be further promoted skin permeation when formulated into liposomes, such as nano-emulsion lipid preparations, it can be expected to prevent or treat the whitening effect and pigmentation by topical administration.

Description

A composition for skin-whitening comprising trimethylphytosphingosine}

The present invention relates to a cosmetic composition for skin whitening and a pharmaceutical composition for preventing or treating pigmentation, and more particularly, to a cosmetic composition for skin whitening comprising trimethyl phytosphingosine as an active ingredient and a pharmaceutical composition for preventing or treating pigmentation. will be.

In humans, skin and hair pigments protect against the harmful effects of sunlight, especially ultraviolet light. For example, people with poor pigmentation (Albinos) are very sensitive to sunlight and are prone to burns. Short wavelength ultraviolet (290-320 nm) and carcinogens form oxygen radicals in the skin, which are known to attack skin cells and age the skin.

An important function of melanin, a pigment in skin or hair, is to remove oxygen radicals and protect the skin from damage. Therefore, high levels of melanin mean that it has an effective response system to protect the skin from physical and chemical toxic substances. However, from the aesthetic point of view of humans, freckles, blemishes, etc. due to melanin deposition are negative factors.

Factors that promote the production of melanin include sunlight (ultraviolet rays) as well as estrogen (estrogen), prostaglandin (prostaglandin). The production and disappearance of melanin is achieved by the following cycles. When melanocytes are stimulated, the amino acid tyrosine contained in the cells binds to tyrosinase, which is activated by stimulation, to produce melanosomes. At this time, tyrosine is combined with oxygen to oxidize and tyrosinase is combined with copper. If the skin lacks copper, it interferes with normal melanin production. Stimulation such as ultraviolet light not only directly affects melanin-producing cells, but also affects melanocyte stimulating hormone (MSH), which stimulates melanin production when the melanocyte stimulating hormone secretion increases. The amino acid called tyrosine contained in the melanocytes is converted into dopa by tyrosinase action and then into dopaquinone by the action of dopaoxidase to produce melanin. The melanin thus produced is circulated to be delivered to the skin cells and the melanin is lost and disappeared together with the epidermal detachment.

The biosynthetic mechanism of melanin has recently been intensively studied in relation to skin cancer, and various melanin-producing inhibitors have been developed from this, and the skin whitening agent or food industry which prevents and improves skin disease treatment drugs in the pharmaceutical industry, blemishes and freckles in the cosmetic industry, etc. Has been applied as a browning inhibitor, etc.

Until now, the following method is known as a method of inhibiting melanin production in cosmetics for whitening or medicines for pigmentation treatment. First, by blocking the ultraviolet rays to remove the main cause of melanin production, this method can be expected to excellent lightening effect by containing a light scattering agent or a light blocking agent in the cosmetic composition. Second, it is a method of inhibiting melanin production by inhibiting the synthesis of core carbohydrates such as glucosamine necessary for tyrosinase to be active. Third, using kojic acid or arbutin is a method of interfering with the function of tyrosinase, an enzyme involved in melanogenesis. Fourth, it has a specific toxicity to melanocytes, such as melanin-producing cells such as hydroquinone, is a method of inhibiting cell division of melanin. Fifthly, there is a method of reducing the generated melanin to decolorize.

Research on such melanogenesis inhibitors has been mainly focused on developing tyrosinase inhibitors, and as representative melanin biosynthesis inhibitors, hydroquinone, ascorbic acid or derivatives thereof, kojic acid, and glutathione Substances having inhibitory activity against tyrosinase, such as arbutin, are known. However, hydroquinone has a problem that the use of skin is very strong because of irritation, and ascorbic acid is easily oxidized, such that discoloration and discoloration of the formulation occur. In addition, kojic acid is unstable in solution, so the stability of the formulation is low and there is a problem of carcinogenicity for the development of thyroid cancer. In addition, in the case of arbutin, its activity is not high, and 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 have high polarity, so that they can be incorporated into cosmetic raw materials. There is a difficult problem (Patent Document 1).

Ceramide or ceramide derivatives such as sphingosine-1-phosphate and phytosphingosine-1-phosphate, collectively referred to as spingolipid, are important lipids that form the biofilm structure of higher cells such as animals, plants and yeast. In addition to the simple structural functions, a lot of researches are being conducted in recent years as bioactive functions are revealed, such as differentiation of cells and acting as an intermediate transporter of a signaling system. In particular, as the function of sphingolipid to exist on the surface of human skin tissue and to prevent moisture dissipation to prevent skin drying, various forms of natural or synthetic sphingolipid have begun to be used as functional compositions of cosmetics. Ceramide is a very important constituent of the outer skin of the skin epidermis, which forms and preserves lipid impermeable membranes with moisture retention capability. Sphingosine-1-phosphate has a known whitening effect (Patent Document 2). However, the sphingosine derivatives are not effective enough, although some whitening effects are known. Therefore, there is a need for the development of a more effective and safe skin whitening effect.

1. Korean Patent Publication 2010-0028202 2. Korean Patent Publication 2003-0087448

Accordingly, the present inventors have conducted research for the development of a material having a whitening effect, and have found a material having an excellent effect of suppressing melanin production, thereby completing the present invention.

Accordingly, it is an object of the present invention to provide a cosmetic composition for skin whitening comprising a substance having an excellent effect of inhibiting melanin production.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating pigmentation, including a substance having an excellent effect of inhibiting melanin production.

In order to achieve the above object, an aspect of the present invention provides a cosmetic composition for skin whitening comprising trimethylphytosphingosine or cyclic trimethylphytosphingosine, a pharmaceutically acceptable salt thereof, or a solvate thereof. do.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating pigmentation including trimethyl phytosphingosine or cyclic trimethyl phytosphingosine, a pharmaceutically acceptable salt thereof, or solvate thereof.

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention are used in the sense that they are generally understood by those of ordinary skill in the relevant field of the present invention unless otherwise defined. Also, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention. The contents of all publications cited herein are hereby incorporated by reference in their entirety.

The present inventors have newly discovered that trimethyl phytosphingosine or cyclic trimethyl phytosphingosine have an effect of inhibiting melanogenesis by studying to develop a substance that is effective in skin whitening, and each of them alone when administered in combination with arbutin It has been found to show a synergistic effect compared to when administered.

Accordingly, in one aspect, the present invention provides a cosmetic composition for skin whitening comprising trimethylphytosphingosine of formula 1 or cyclic trimethylphytosphingosine of formula 2, a pharmaceutically acceptable salt thereof, or solvate thereof:

[Chemical Formula 1]

(2)

In another aspect, the present invention provides a pharmaceutical composition for preventing or treating pigmentation, comprising trimethyl phytosphingosine of Formula 1 or cyclic trimethyl phytosphingosine of Formula 2, a pharmaceutically acceptable salt thereof, or solvate thereof. :

[Chemical Formula 1]

(2)

The pigmentation refers to a skin disease caused by pigmentation, and includes, for example, blemishes, freckles, otamoban, blotch, vitiligo and the like.

The compound of Formula 1 included as the active ingredient may be prepared using conventional knowledge known in the field of organic chemistry, and may be prepared using, for example, the method disclosed in Korean Patent Publication No. 2003-0014780. .

The compound of formula 2 included as the active ingredient may be prepared using conventional knowledge known in the field of organic chemistry, for example, may be prepared by the following method.

One equivalent of boc anhydride is added to a methanol solution of phytosphingosine in the presence of one equivalent of K ₂ CO _{3 and} stirred at room temperature for 24 hours. The solvent was removed and extracted from water and ethyl acetate solution to obtain N-Boc phytosphingosine, which was dissolved in methylene chloride (MC), followed by TBDPS-Cl (1.05 equiv), imidazole (1.05 equiv), and 4-DMAP (catalyst) After the addition, the mixture was stirred at room temperature for 12 hours. The reaction solution was treated with an aqueous solution of conc-NH ₄ Cl and extracted to obtain 1-TBDPS-ON-Boc phytosphingosine. The compound protected with 3,4-acetonide was obtained, the solvent was distilled under reduced pressure, then dissolved in THF solvent, and then treated with 1 equivalent of Bu ₄ NF at room temperature to remove the 1-TBDPS group. Ethyl acetate is added, and the liquid product obtained by washing with water several times is added with CH ₃ CN to crystallize to obtain a 3,4-acetonide-N-Boc phytosphingosine material. The obtained 3,4-acetonide-N-Boc phytosphingosine compound was dissolved in methylene chloride, and then treated with 1.2 equivalents of PPh ₃ I ₂ (1.2 equivalents) and amidazole (1.2 equivalents), followed by stirring for 12 hours at room temperature, followed by addition of water. Extraction with methylene chloride affords 1-iodophytosphingosine compound. The obtained 1-iodophytosphingosine compound was dissolved in methanol, treated with 20 equivalents of 48% HF aqueous solution, heated to 50 ° C, reacted for 12 hours, and then the solvent was removed, treated with an aqueous NAHCO ₃ solution, extracted with ethyl acetate, and then compound 1,3 Cyclic phytosphingosine was obtained. After dissolving 1,3-cyclic phytosphingosine in methanol, the mixture was treated with KeCO (10 equivalents) and me-I (10 equivalents), and then reacted at 50 ° C. for 12 hours, treated with an aqueous solution, and extracted with ethyl acetate. Got. Its purification was recrystallized from acetone to obtain the compound of formula 2 as a white solid.

Pharmaceutically acceptable salts of the compounds of Formula 1 or 2, or solvates thereof may be appropriately prepared or selected by those skilled in the art of organic chemistry using knowledge known in the art.

The pharmaceutically acceptable salt may exist as an acid addition salt in which the compound of the above formula (1) or (2) forms a salt with a free acid. The compounds of formula (I) or (II) may form pharmaceutically acceptable acid addition salts according to conventional methods known in the art. The free acid may be an organic acid or an inorganic acid, and the inorganic acid may be hydrochloric acid, bromic acid, sulfuric acid, or phosphoric acid, and the organic acid may be citric acid, acetic acid, lactic acid, tartaric acid, or tartariac acid. ), Maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, galluxuronic acid, embon acid, Glutamic acid or aspartic acid, etc. can be used. The compounds of formula (I) or (II) according to the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates which can be prepared by conventional methods.

The compounds of Formula 1 and Formula 2 may be stabilized by an anion paired with an ammonium cation in the compound, and the anion may be any anion that can be paired with an ammonium cation while being pharmaceutically acceptable, eg a yaw example iodide (I ^-), sulfonate (SO ₃ ^2-), chloride (Cl ^-), etc., but it is not limited to this.

Hereinafter, the cosmetic composition for skin whitening and the pharmaceutical composition for preventing or treating pigmentation are collectively referred to as "composition according to the present invention".

It was demonstrated in the following examples that the trimethyl phytosphingosine (TMP) and cyclic trimethyl phytosphingosine (cyclic TMP) have a whitening effect by inhibiting melanogenesis. Specifically, the melanin production inhibitory effect of the arbutin solution known as a whitening substance and the said trimethyl phytosphingosine and cyclic trimethyl phytosphingosine with Melan-A cell line was tested (Experimental example 1). As a result, trimethyl phytosphingosine and cyclic trimethyl phytosphingosine showed a significantly superior effect on the inhibition of melanin production compared to arbutin, and trimethyl phytosphingosine showed better melanin production inhibition rate than cyclic trimethyl phytosphingosine.

The composition according to the present invention may further include other skin lightening agents known to have a skin lightening effect. In particular, the composition according to the present invention exhibits a synergistic whitening effect in the case of further containing arbutin as compared to the case of containing arbutin or the compound alone (Experimental Examples 2-2 and 2-3). Therefore, the composition according to the present invention preferably further comprises arbutin.

In addition, the cosmetic composition for whitening according to the present invention may be prepared in various forms, according to a conventional cosmetic production method. For example, the cosmetic composition according to the present invention may also be prepared in the form of a bath liquid, which may be used diluted with conventional bath water, cleansing liquid, astringent liquid and moisturizing liquid. In addition, the cosmetic composition according to the present invention may be prepared in the form of skin lotion, milk lotion (nutrition lotion), whitening cream, or whitening essence, and the like, and preferably, in order to promote the effect by increasing transdermal absorption, Or in the form of transdermal absorption accelerators such as nanoemulsions.

The pharmaceutical composition for preventing or treating pigmentation according to the present invention includes, but is not limited to, oral administration, injection, suppository, transdermal administration, and non-administration, including a pharmaceutically acceptable carrier. It may be formulated into a formulation. Preferably, the pharmaceutical composition may be formulated in a form suitable for topical application to the skin site. Such topical administration preparations include liposomes, nanoemulsions, ointments, emulsions, suspensions, solutions, lotions, and the like, but are not limited thereto. Preferably, in order to promote the effect by increasing transdermal absorption, liposomes or It may be formulated in the form of a transdermal absorption promoting agent such as a nanoemulsion. In formulating the compositions, pharmaceutically acceptable carriers, diluents, or additives appropriate for the preparation of each agent known in the art of pharmacy may be prepared by those skilled in the art as appropriate.

Such formulations may be appropriately prepared by one skilled in the art according to conventional methods known in the art, see Remington's Pharmaceutical Science, 15th Edition, 1975, Mack Publishing Company Easton, Pennsylvania 19042 (Chapter 87; Blaug, Seymour). Can be.

The composition according to the present invention may be more preferably formulated in the form of a nanoemulsion. When formulated into a nanoemulsion, transdermal absorption of the active ingredient may be further promoted. The nanoemulsion may be any nanoemulsion known in the art, but preferably 1-10 parts by weight of oil; 5-40 parts by weight of PEG-8 caprylic / capric glyceride; 0.5-10 parts by weight of lecithin; 0.5-10 parts by weight of a skin permeation promoter selected from the group consisting of poloxamer, polysorbate 20, nerolidol, 2-n-nonyl-1,3-dioxolane, urea, limonene, and combinations thereof; And 20-90 parts by weight of water. The method for producing such a nanoemulsion is described in Korean Patent Publication No. 2010-0018118, which is incorporated by reference in its entirety.

The composition according to the present invention may contain the compound of Formula 1 or 2 in the range of about 0.1% to 10% by weight, preferably 0.5% to 5% by weight, based on the total composition And depending on the type of agent.

The pharmaceutical composition for treating or preventing pigmentation according to the present invention is a compound of Formula 1 or 2, based on an adult at 0.0001 to 1000 mg / kg per day, preferably at a dosage of 0.001 to 1000 mg / kg per day. May be administered. In the case of topical administration, the compound of Formula 1 or 2 may be administered by applying once or twice a day to a desired site for treating or preventing pigmentation. When the active ingredient is 1% by weight, the daily application amount is about 0.5-3 mg, and may be increased or decreased depending on the area of the application site. Dosage and frequency of the compound of Formula 1 or 2 may be appropriately increased or decreased depending on the age, sex, degree of progression of pigmentation, administration route, formulation, and the like of the patient.

As described above, the composition according to the present invention is not only effective in the prevention or treatment of the whitening effect and pigmentation by the melanin production inhibitory effect, but also can exhibit a more effective melanin suppression effect by constructing a complex composition with arbutin . In addition, the composition according to the present invention can be further promoted skin permeation when formulated into liposomes, such as nano-emulsion lipid preparations, it can be expected to prevent or treat the whitening effect and pigmentation by topical administration.

FIG. 1 is a graph showing the content of arbutin penetrating the skin over time as a result of performing a Franz diffusion cell experiment using an arbutin aqueous solution and arbutin nanoemulsion using a mouse skin.
2 is a solution of TMP, cyclic TMP, and arbutin, and TMP-containing liposomes, each diluted 2 folds in Melan-a cell line, followed by incubation in 37 ° C., 5% carbon dioxide environment for 5 days, to produce melanin. It is a graph showing the inhibition rate of production.
FIG. 3 shows the inhibition rate of melanin production generated after culturing for 5 days in 37 ° C. and 5% carbon dioxide environment by adding two-fold dilution of arbutin aqueous solution, arbutin-containing liposome, and arbutin and TMP-containing liposome to Melan-a cell line. One graph.
Figure 4 shows the inhibition rate of melanin production generated after culturing for 5 days in 37 ℃, 5% carbon dioxide environment by adding two-fold dilution of arbutin aqueous solution, normal whitening toner, TMP and arbutin-containing nanoemulsion to B16 melanoma cell line It is a graph.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these embodiments are provided to aid understanding of the present invention, and the scope of the present invention is not limited thereto in any sense.

<Definition of Abbreviation>

IPM: Isopropyl Myristate

LAS: P EG-8 caprylic / capric glyceride

1,3-BG: 1,3-butylene glycol

TMP: trimethyl phytosphingosine

cylic TMP, C-TMP: cyclic trimethylphytosphingosine

Comparative Example 1: Preparation of Arbutin-containing Liposomes

Liposomes containing arbutin were prepared. The preparation method of liposomes was prepared by sonication, and the liposome composition was 2% by weight arbutin, 4% by weight lecithin, 10% by weight ethanol, 2% by weight poloxamer, 2% by weight tween 20 and the rest was purified water. After the lecithin was dissolved in ethanol, a solution of arbutin, poloxamer, and tween 20 was slowly added to the lecithin solution, followed by vigorous stirring. After stirring for 30 minutes or more, sonication was performed for 2 minutes to prepare an arbutin-containing liposome.

Example 1 Preparation of TMP-Containing Liposomes

Liposomes containing trimethylphytosphingosine (TMP) were prepared. The preparation method of liposomes was prepared by an ultrasonic treatment method, and the rest of the liposome was 0.01 wt% TMP, 4 wt% lecithin, 10 wt% ethanol, 2 wt% poloxamer, and 2 wt% tween 20 as purified water. After dissolving lecithin and TMP in ethanol, a solution of poloxamer and tween 20 dissolved in the lecithin solution was stirred vigorously. TMP-containing liposomes were prepared by sonication for 2 minutes after stirring for at least 30 minutes.

Example 2: Preparation of Arbutin + TMP Containing Liposomes

Liposomes containing arbutin and TMP were prepared. The liposome was prepared by sonication, and the liposome composition was 2% by weight arbutin, 0.01% by weight TMP, 4% by weight lecithin, 10% by weight ethanol, 2% by weight poloxamer, 2% by weight tween 20 and the rest was purified water. It was. After dissolving lecithin and TMP in ethanol, a solution of arbutin, poloxamer, and tween 20 was slowly added to the lecithin solution and stirred vigorously. After stirring for 30 minutes or more, sonication was performed for 2 minutes to prepare arbutin and TMP-containing liposomes.

Example 3: Preparation of Arbutin + TMP-Containing Nanoemulsion

Nanoemulsions containing arbutin and TMP were prepared. The composition of the nanoemulsion was 2 wt% arbutin, 0.01 wt% TMP, 7.4 wt% oil (IPM), 35.8 wt% LAS, 4 wt% lecithin, 10 wt% 1,3-BG and the rest was purified water. An arbutin solution in which arbutin was dissolved in distilled water was added to the solution in which TMP, oil, LAS, and lecithin were dissolved in 1,3-BG while stirring. It was gently stirred by hand to form a nanoemulsion.

Comparative Example 2: Preparation of Arbutin-Containing Nanoemulsion Ampoule Formulations

To make a whitening nanoemulsion ampoule formulation, the oil content is adjusted to 3% by weight, and the nanoemulsion ampoule containing 5% by weight of each plant extract (botan bark, dianthus, willow bark, and persimmon leaf) with known whitening efficacy Was prepared. 2 wt% arbutin, 4 wt% lecithin, 3 wt% IPM, 10 wt% 1,3-BG, 25 wt% LAS, 2 wt% poloxamer, 2 wt% tween 20, 5 wt% Botanfi, 5 wt% Twin Blood, 5% by weight willow bark extract, 5% by weight persimmon leaf extract and the rest was used purified water. Specifically, after dissolving lecithin in 1,3-BG, IPM and LAS were added. After the mixture was thoroughly mixed, an aqueous arbutin solution and persimmon leaf extract, dianthus extract, botan bark, willow bark extract) dissolved in purified water were added with stirring and stirred at room temperature for 30 minutes to prepare a nanoemulsion. Nano-emulsions were prepared by adding poloxamer and Tween 20 as skin permeation accelerators.

Example 4 Preparation of Arbutin and TMP Containing Nanoemulsion Ampoule Formulations

2 wt% arbutin, 0.01 wt% TMP, 4 wt% lecithin, 3 wt% IPM, 10 wt% 1,3-BG, 25 wt% LAS, 2 wt% poloxamer, 2 wt% tween 20, 5 wt% Botanfi , 5% by weight dianthus, 5% by weight willow bark extract, 5% by weight persimmon leaf extract and the rest was used purified water. Specifically, TMP, IPM, and LAS were added after dissolving lecithin in 1,3-BG. After the mixture was thoroughly mixed, an aqueous arbutin solution and persimmon leaf extract, dianthus extract, botan bark, willow bark extract) dissolved in purified water were added with stirring and stirred at room temperature for 30 minutes to prepare a nanoemulsion. Nano-emulsions were prepared by adding poloxamer and Tween 20 as skin permeation accelerators.

Experimental Example 1 Skin Permeation Experiment of Arbutin-Containing Nanoemulsion

Skin permeation experiments were performed using a hairless mouse on the free solution containing 2% by weight arbutin and the arbutin-containing nanoemulsion prepared in Comparative Example 2. The skin at the back and belly of the hairless mouse was used for the experiment, and the skin was cut to the appropriate size after scissors were excised near the tail of the mouse. After removing the fat present in the skin, it was placed in a Franz diffusion cell and 1.0 ml of arbutin nanoemulsion or arbutin aqueous solution was placed on the skin. 0.6 mL was taken from the diffusion cell at predetermined time intervals, and the experiment was repeated to supplement 0.6 mL. After skin separation after 23 hours, the skin was thoroughly washed with distilled water and PBS buffer, and then 3 mL of PBS buffer was added to homogenize for 3 minutes, centrifuged, and the supernatant was taken to measure arbutin content. Quantification of arbutin that passed through the skin in addition to arbutin present in the skin was determined by HPLC method.

The results are shown in Fig.

FIG. 1 is a graph showing the content of arbutin penetrating the skin over time as a result of performing a Franz diffusion cell experiment using an arbutin aqueous solution and arbutin nanoemulsion using a mouse skin.

According to the results of FIG. 1, the aqueous solution containing 2% by weight arbutin hardly caused skin penetration, whereas the nanoemulsion containing 2% by weight arbutin can observe significant skin penetration over time. It is difficult to expect the whitening effect because it is not possible to penetrate the skin with arbutin solution, but if the cosmetic preparation with the nanoemulsion formulation can increase the skin permeation can be expected whitening effect. Thus, nanoemulsions containing arbutin and TMP can be excellent whitening cosmetics.

Experimental Example 2: In vitro whitening efficacy measurement

Two cell lines were used to measure whitening efficacy. The whitening efficacy was measured by using melan-a (Non-tumorigenic cells) cell line before completely differentiated into cancer cells and B16 melanoma cell line which can cause metastasis. Melan-a cell line is a cell line closer to the normal human melanocytes (melanocytes).

Experimental Example 2-1: Determination of the whitening efficacy of each of the aqueous solution of TMP, cyclic TMP, and arbutin

TMP and cyclic TMP were dissolved in ethanol, arbutin was dissolved in purified water, and the whitening effect was measured. In addition, the whitening efficacy was also measured for the TMP-containing liposome prepared in Example 1.

After culturing the Melan-a cell line in 96 wells, each sample was added twice with dilution, incubated for 5 days at 37 ° C. and 5% carbon dioxide, and then measured by absorbance after 5 days. . Saline was used as a control. The results of calculating the inhibition rate of melanin production relative to the control group are shown in Table 1 and FIG. 2.

2 is a solution of TMP, cyclic TMP, and arbutin, and TMP-containing nanoemulsion, respectively, diluted 2-fold in Melan-a cell line, followed by incubation in 37 ° C., 5% carbon dioxide environment for 5 days, and then externally generated melanin. It is a graph showing the inhibition rate of production.

According to the results of FIG. 2, arbutin, a tyrosinase inhibitor, shows whitening efficacy at a very high concentration, whereas TMP shows whitening activity at a very low concentration. Cyclic TMP showed lower whitening activity than TMP but significantly higher whitening activity than arbutin. TMP-containing nanoemulsions had the highest whitening activity.

Comparison of Whitening Efficacy of Arbutin and TMP Using Melan-a Cells Concentration (ug / ml), melanin production inhibition rate (% by weight) density
Group 0.15 0.3 0.6 1.2 2.5 5 10 20 50 100 200 Arbutin - - - - 0 13 26 42 49 52 59 TMP 15 26 30 36 52 55 80 80 cyclic-TMP 5 10 15 22 30 45 60 75 TMP-
Liposome 25 38 51 60 72 80 85 85

Experimental Example 2-2: Determination of the whitening efficacy of arbutin and / or TMP liposomes

For the arbutin aqueous solution, the arbutin-containing liposome prepared in Comparative Example 1, the arbutin and TMP-containing liposome prepared in Example 2, the whitening effect was measured in the same manner as in Experimental Example 2-1.

The results of calculating the inhibition rate of melanin production for the control group are shown in Table 2 and FIG. 3.

FIG. 3 shows the inhibition rate of melanin production generated after culturing for 5 days in 37 ° C. and 5% carbon dioxide environment by adding two-fold dilution of arbutin aqueous solution, arbutin-containing liposome, and arbutin and TMP-containing liposome to Melan-a cell line. One graph.

Experimental Example 2-3: Determination of the whitening efficacy of arbutin and TMP nanoemulsion

Since nanoemulsion is easier to mass-produce and better skin penetration than liposomes, arbutin and TMP-containing nanoemulsion cosmetics were prepared and compared with conventional arbutin whitening cosmetics. The whitening efficacy was measured in the same manner as in Experimental Example 2-1, but the whitening efficacy was measured using B16 melanoma cell line instead of melan-a as a cell.

Whitening toner (2% by weight arbutin, 10% by weight 1,3-BG, 5% by weight botanica, 5% by weight persimmon leaf) containing a 2% by weight aqueous solution of arbutin, an arbutin and a whitening efficacy additive, the concentration of functional whitening cosmetics as a sample. , 5 wt.% Dianthus, 5 wt.% Willow bark, remaining water purified), and the whitening activity of the arbutin and TMP-containing nanoemulsion ampoules of Example 4 was measured.

The results of calculating the inhibition rate of melanin production relative to the control is shown in Figure 4 below.

Figure 4 shows the inhibition rate of melanin production generated after culturing for 5 days in 37 ℃, 5% carbon dioxide environment by adding two-fold dilution of arbutin aqueous solution, normal whitening toner, TMP and arbutin-containing nanoemulsion to B16 melanoma cell line One graph.

According to the results of FIG. 4, similar to those using the Melan-a cell line, the arbutin solution containing only 2% by weight arbutin shows weak whitening activity at high arbutin concentration, whereas the TMP + arbutin nanoemulsion ampoule shows significantly higher whitening activity than the arbutin solution. It was found to have. Normal whitening toner showed slightly higher whitening activity compared to arbutin solution. These results indicate that arbutin and TMP-containing nanoemulsions not only promote skin permeation but also whitening efficacy in vitro due to the combination of arbutin and TMP and the properties of the nanoemulsion.

Claims (8)

A cosmetic composition for skin whitening comprising trimethyl phytosphingosine of Formula 1 or cyclic trimethyl phytosphingosine of Formula 2, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

(2)

A pharmaceutical composition for preventing or treating pigmentation, comprising trimethyl phytosphingosine of Formula 1 or cyclic trimethyl phytosphingosine of Formula 2, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

(2)

The pharmaceutical composition according to claim 2, wherein the pigmentation is a blemish, freckles, otamoban, blotch, or vitiligo. The composition according to any one of claims 1 to 3, further comprising arbutin. 4. A composition according to any one of claims 1 to 3, wherein said composition is formulated as liposomes or nanoemulsions. According to claim 5, The nanoemulsion is 1-10 parts by weight of oil; 5-40 parts by weight of PEG-8 caprylic / capric glyceride; 0.5-10 parts by weight of lecithin; 0.5-10 parts by weight of a skin permeation promoter selected from the group consisting of poloxamer, polysorbate 20, nerolidol, 2-n-nonyl-1,3-dioxolane, urea, limonene, and combinations thereof; And 20-90 parts by weight of water. The composition of claim 4 wherein the composition is formulated as liposomes or nanoemulsions. According to claim 7, wherein the nanoemulsion is 1-10 parts by weight of oil; 5-40 parts by weight of PEG-8 caprylic / capric glyceride; 0.5-10 parts by weight of lecithin; 0.5-10 parts by weight of a skin permeation promoter selected from the group consisting of poloxamer, polysorbate 20, nerolidol, 2-n-nonyl-1,3-dioxolane, urea, limonene, and combinations thereof; And 20-90 parts by weight of water.

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