WO2006080589A1

WO2006080589A1 - Sphingolipid-peg derivatives and composition for skin external use containing the derivatives

Info

Publication number: WO2006080589A1
Application number: PCT/KR2004/003382
Authority: WO
Inventors: Sungjin Park; You-A Hwang; Jinwook Kim; Changseo Park
Original assignee: Doosan Corporation
Priority date: 2004-12-21
Filing date: 2004-12-21
Publication date: 2006-08-03
Also published as: WO2006080589A9

Abstract

Disclosed are sphingolipid-PEG derivatives, which comprise sphingolipid selected from the group consisting of N-acetylphytosphigosine, N-acetylsphiganine and N-acetylsphingadiene and polyethylene glycol, and compositions for skin external use containing the derivatives. The sphingolipid-PEG derivatives and the compositions exhibit an improved skin whitening effect. Further, the derivatives and compositions show an improved solubility of sphingolipid and a decreased toxicity and, accordingly, can be used broadly.

Description

[DESCRIPTION]

[Invent ion Tit Ie]

SPHINGOLIPID-PEG DERIVATIVES AND COMPOSITION FOR SKIN EXTERNAL USE CONTAINING THE DERIVATIVES

[Technical Field]

The present invent ion relates to sphingol ipid derivat ives and a composit ion containing the derivat ives . More speci fical ly, the present invent ion relates to sphingol ipid-polyethylene glycol derivat ives formed by combining sphingol ipid selected from a group consist ing of N- acetylphytosphingosine, N-acetylsphinganine and N-acetylsphingadiene with polyethylene glycol and a skin whitening use of the derivat ives .

[Background Art]

<2> Hyperpigmentat ion in the skin gives a serious mental stress from a skin esthet ic view and also a serious hindrance to a social act ivity. In addit ion, according to social changes of that a white and del icate skin is a standard of beauty, developments of a whitening agent are act ively performed. <3> Recent researches of the whitening agent are focused on control l ing various factors part icipat ing in a melanin synthesis process. For example, the researches are progressed to a ultraviolet block, a control of cytokine or hormone, a control of an internal signal of melanocyte, an inhibit ion of act ivity of tyrosinase enzyme, an inhibit ion of movement of melanosome, and a quick desquamat ion of melanin pigmented skin cel l .

<4> Sphingol ipid is known as a material part icipat ing in a signal transduction in a cel l and thus performing an important role in growth, di fferent iat ion and death of the cel l . Ceramide is the most exist ing l ipid in the skin and known as a material suppressing an evaporat ion of moisture from the skin and prevent ing an aging and a cutaneous disorder . In addit ion, it is known that phytosphingosine, which is a long chain base of sphingol ipid, or acetylated derivat ives thereof have excel lent ant ibacterial and ant i^¬ inflammatory effects and part icipate in biosynthesis of ceramide in the skin. However , a research of ceramide or sphingol ipid derivat ives in kerat inocytes has been actively progressed, but a research of melanin synthesis is not current ly much progressed.

<5> Kim, et al . (Kim, Dong-Seok, Cel lular signal ing 14 (2002) 779-785) performed a research on a participation in melanin synthesis using sphingol ipid derivat ives for the first time, and reported that ceramide derivatives (C2 ceramide) exhibit an excellent effect of suppressing melanin synthesis at 1 ~ 10 μ M, compared to koj ic acid. In addition, it was reported that sphingosine-1-phosphate suppresses the melanin synthesis through a control of a signal transduction process of the melanin synthesis. Meanwhile, Doosan Corporation proved N-acetylphytosphingosine, which is a derivative of phytosphingosine, to have a whitening effect and fi led the patent appl ication regarding it (Korean Patent Appl ication No. 2002-72043) .

<6> Meanwhi le, the sphingol ipid has a very low solubi l ity, so that it has many restrains when it is used in many formulations.

<7> Polyethylene glycol is a polymer having a structure of HO- (CH2CH2θ)nCH2CH₂-OH, frequently used in foods or cosmet ics and has an effect of retarding a degradation of an active material , so that it has been much used in a pharmaceutical prescript ion. The polyethylene glycol is an innoxious polymer , has a good solubi l ity, and has no antigenicity and is easi ly removed in the human body, so that it is a suitable material for the purposes. Since the polyethylene glycol has hydroxy groups at both ends, monomethoxy polyethylene glycol (CH3θ-(CH2CH2θ)nCH2CH2-OH) having one end inactivated is actual ly much used in PEGylation and those having the molecular weight of up to 30,000 Daltons are used. In order to bind monomethoxy polyethylene glycol to a medicine, a hydroxy group at one end having no methoxy connected thereto is activated and connected by using diverse chemicals.

<8> Lewis S. L. et al . (U.S. Patent No. 5,820,873, 1995) tried to synthesize polyethylene glycol-ceramide derivatives and to apply them to 1 iposome. [Disclosure] [Technical Problem]

<9> The object of the present invent ion is to prevent hyperpigmentat ion of melanin by using sphingol ipid derivat ives and thus suppressing an act ivity of tyrosinase, thereby prevent ing skin pigmentary symptoms such as melasma, ephel is , seni le pigment spots and skin hyperpigmentat ion, etc. The other object of the invent ion is to provide a composit ion for skin external use having such effects .

[Technical Solut ion]

<10> In order to accompl ish the object , there is provided a sphingol ipid- polyethylene glycol derivat ive formed by combining sphingol ipid selected from a group consist ing of N-acetylphytosphingosine, N-acetylsphinganine and N- acetylsphingadiene wi th polyethylene glycol .

<11> The sphingol ipid-polyethylene glycol derivat ive is one of compounds having fol lowing formulas 1 to 3.

[Chemistry Figure 1]

<13>

[Chemistry Figure 2]

<15> [Chemi stry Figure 3]

<17>

<i8> In the above formulas, Ri is independent ly hydrogen, alkyl group of Ci-

4o, alkenyl group of Ci-₄₀, alkynyl group, acyl group or aryl group of Ci-₄o. <19> When Ri is acyl group (COR2) , R2 is alkyl group, alkenyl group, alkynyl group or aryl group. <20> X is -NR3-, -0-, -S- or -Xi-alk-X₂-, wherein R₃ is hydrogen, alkyl group, acyl group or aryl group of Ci-β, Xi and X2 are independent ly amino group, amido group, carboxy group, cabamate group, carbonyl group, urea or phosphoro-, and alk i s alkylene of Ci-6.

<2i> The sphingol ipid-polyethylene glycol derivat ive of the invent ion has polyethylene glycol having a molecular weight of 550 ~ 10,000Da, more preferably 700-5,000Da and an end having a methoxy group replaced. <22> A composit ion for skin external use according to the invent ion contains the sphingol ipid-polyethylene glycol derivat ive as described above as an effect ive ingredient . <23> The composit ion for skin external use according to the invent ion suppresses an act ivity of tyrosinase. <24> The composit ion for skin external use according to the invention is used for skin whi tening. <25> In the composit ion for skin external use according to the invent ion, the composit ion is a cosmet ics composit ion. <26> According to the invention, the composition for skin external use contains 0.005 ~ 10 wt .% of the sphingol ipid-polyethylene glycol derivat ive. <27> A method of suppressing an act ivity of tyrosinase according to the invent ion uses the sphingol ipid-polyethylene glycol derivat ive. <28> A method of suppressing a melanin synthesis according to the invent ion uses the sphingol ipid-polyethylene glycol derivat ive.

[Advantageous Effects] <29> The sphingol ipid-polyethylene glycol derivat ives of the invent ion inhibit the melanin synthesis by suppressing the tyrosinase act ivity, thereby prevent ing and treat ing skin pigmentary symptoms such as melasma, ephel is, seni le pigment spot , and skin hyperpigmentat ion, etc.

[Descript ion of Drawings] <30> FIG. 1 is a photograph showing a melanin product ion inhibit ing effect of a sphingol ipid-polyethylene glycol derivat ive according to an embodiment of the invent ion; <3i> FIG. 2 is a graph showing a standard curve of a variat ion of a OD value (475 nm) according to the amounts of tyrosinase; and <32> FIG. 3 is a graph showing a tyrosinase act ivity inhibiting effect of a sphingol ipid-polyethylene glycol derivative according to an embodiment of the invent ion. [Best Mode] <33> Hereinafter , preferred embodiments of the present invent ion wi l l be described in detai l . <34> The invent ion is characterized in that a whitening effect is increased by combining polyethylene glycol with sphingol ipid. The inventors proved that sphingol ipid-polyethylene glycol derivat ives have an excel lent whitening effect , compared to sphingol ipid itsel f. <35> A typical example of the sphingol ipid-polyethylene glycol of the invent ion is those that R₁ is independent ly hydrogen, alkyl group or acyl group, X is succinate, and the polyethylene glycol has a molecular weight of 750-5,000 and its one end has a methoxy group replaced.

<36> The sphingol ipid-polyethylene glycol derivat ive of the invent ion may be manufactured by react ing sphingol ipid with polyethylene glycol previously act ivated in a solvent under a catalyst . <37> The manufacturing method is more specifical ly described as fol lows. First ly, polyethylene glycol is act ivated. Succinic anhydride is added to the polyethylene glycol in the organic solvent and thus alcohol group is converted to carboxyl group. In the polyethylene glycol having carboxyl group replaced, an acid port ion is act ivated using triethylamine and p- toluenesul fonylchloride, sphingol ipid is added to the act ivated solut ion by a smal l amount , the added solut ion is warmed and thus the 24 hours react ion is completed.

<38> The compound made by the above method is extracted with an organic solvent such as chloroform or a mixing solvent of chloroform/methanol and puri fied with an adsorpt ion-chromatography by si l ica gel .

<39> The composit ion of the invent ion is characterized in that it is a composit ion for skin external use. Part icularly, the composit ion may be a cosmet ics composit ion and is preferably water lot ion, mi lk lot ion, massage cream, nutri-cream, gel , pack or skin ropy type of cosmetics formulat ion.

<4o> The composit ion of the invent ion contains 0.005 - 10 wt .% of the above sphingol ipid-polyethylene glycol derivat ive. A whi tening effect of the invent ion can be achieved when a content of the derivat ive is 0.005 wt .% or more , and a formulat ion stabi l ity is excel lent when the content is 10 wt .% or less .

<4i> In the sphingol ipid-polyethylene glycol derivat ives of the invent ion, a molecular weight of the polyethylene glycol is preferably 550 ~ 10,000Da, more preferably 700 ~ 5,000Da. The range of the molecular weight is an opt imal range to achieve an object to combine the polyethylene glycol with sphingol ipid in the invent ion.

<42> In addit ion, the composit ion may be a transdermal administrat ion type formulat ion such as lot ion, ointment , gel , cream, patch or aerosol .

<43> The skin color of human is determined by various skin ingredients . Among them, melanin produced by melanocyte plays the most important role. The melanocyte of the skin is regulated to exhibit a certain degree of the skin color by an inherited character according to races . However , when it is stimulated by ultraviolet , stress, cytokine, and melanin synthesis inducing materials such as a melanocyte-stimulat ing hormone (MSH) , melanin synthesis is increased and the synthesized melanin moves to adjacent kerat inocytes via melanosomes and is final ly subject to a process of desquamation from the skin.

<44> General ly, a temporary change of the skin color returns to the previous skin color through the above mechanism as t ime goes by. However , when the skin is exposed to sunl ight for a long time, it often occurs that the skin color is irreversibly changed to a black.

<45> Melanin is synthesized in melanosome in the melanocyte, which is originated in endoplasmin reticulum, and regularly accumulated by an internal structure of the melanosome. Tyrosinase which converts tyrosine into melanin is produced in golgi apparatus and moves to the melanosome. In the melanosome prior to maturity, tyrosine causes an oxidation-reaction by tyrosinase and biosynthesis of melanin starts. The melanosom in which the melanin synthesis begins passes through about four steps of maturity processes and then generation of matured melanosome is completed. The matured melanosome moves to adjacent kerat inocytes, and the skin color is determined according to the number , sizes and distributions of the melanin in the keratinocytes. The melanosome moves from a base layer of epidermis to kerat inocyte, and to stratum corneum whi le protecting the kerat inocyte. During moving, the melanosome is disintegrated, but the melanin maintains at its un- disintegrated state and is final ly desquamated from the skin.

<46> The tyrosinase playing the most important role in the melanin biosynthesis is synthesized in the golgi apparatus, and then moves to the melanosome whi le being subject to a glycosylation process. After moving to the melanosome, it is converted into an activated form by phosphorylation.

<47> The melanin synthesis begins when the activated tyrosinase causes an oxidation-reaction using the tyrosine as a substrate. The tyrosine is converted into DOPA (dihydroxyphenylalanine) by tyrosinase, which is again converted into DOPA quinone by tyrosinase. The DOPA quinone couples with glutathione or cysteine and thus is converted into cysteinyl DOPA and final ly into pheomelanin. On the other hand, after the DOPA quinone is converted into DOPAchrome, it goes through 5,6-dihydroxyindole then is converted into indole-5,6-quinone by an action of the tyrosinase, and final ly into eumelanine. The tyrosinase participates in the last stage as wel l as in the early stage of the melanin synthesis react ion and thus is known as the most important enzyme of the melanin synthesis process. Many materials having an effect of inhibit ing melanin formation were developed to inhibit an activity of tyrosinase. The composition of the invention contains also sphingol ipid such as N-acetylphytosphingosine, etc. inhibit ing the activity of tyrosinase.

<48> Each of eumelanin and pheomelanin synthesized in the melanocyte exists in a proper rat io different from each other according to races or parts in the human body, thereby causing a difference of the skin colors. The eumelanin exhibits black and brown colors, and the pheomelanin exhibits an orange color and is synthesized from two kinds of proteins, i .e. , tyrosine and cysteine.

<49> The melanin functions to protect the skin from ultraviolet . It is a useful material to protect skin organs under the dermis and simultaneously to catch act ive oxygen and free radicals generated from the skin, thereby protect ing the proteins and nuclei acids. However , when melanin having the useful functions as described above is abnormal ly produced and pigmented to the skin, melasma, ephel is, and skin dyspigmentat ion occur .

<50> When the composition of the invention is a transdermal administration type formulat ion of pharmaceut ical composition, a preferred dosage is 0.001-1000 mg/body weight (kg) two times per a day, based on the composit ion containing 0.005 - 10 wt .% of N-acetylphytosphingosine-polyethylene glycol derivat ive. [Mode for Invention]

<5i> Hereinafter, preferred examples of the invention wi l l be more specifical ly explained. However , the invention is not l imited to such examples. <52> Examples

<53> <Manufacturing example 1: manufacture of sphingolipid-polyethylene glycol derivatives of the invention>

<54> 5 g (0.0067 mole) of methoxy polyethylene glycol was dissolved in pyridine solvent under atmosphere of nitrogen gas and 6.67 g (0.067 mole) of succinic anhydride was slowly added to the solution. After then, the solution was subject to a reaction at room temperature for 24 hours under a state that the l ight was blocked. After the completion of the react ion, pyridine was converted into a salt form by adjusting to pH 2 by adding hydrochloric acid, and was extracted and removed by adding chloroform and water . Simi larly, an excessive succinic anhydride was also extracted and removed with the water layer . 1 g (0.0011 mole) of methoxy polyethylene glycol-carboxy1 acid obtained as above was dissolved in dichloromethane solvent under atmosphere of nitrogen gas and carboxyl group was act ivated by using 0.17 ml (0.0017 mole) of triethylamine and 2.11 g (0.011 mole) of p-toluenesulfonylchloride. After that , N-acetylphytosphingosine 0.22 g (0.0011 mole) was slowly added to the solut ion and then was subject to a reaction for 24 hours whi le warming. After the completion of the reaction, the react ion was stopped by extracting with disti l led water , and purified with an adsorpt ion-chromatography by si l ica gel , so that N-acetylphytosphingosine-polyethylene glycol derivative of the invention was obtained. The succinate, which was introduced in methoxy polyethylene glycol by reacting with succinic anhydride, was confirmed with IH NMR (δ = 2.6 ppm, t , 4H) , and final ly methylene (δ = 1.2 ppm, m, 48H and d = 0.9 ppm, t , 6H) of N-acetylsphingosine and ethoxy (δ = 3.6 ppm, m, 64H) and methoxy (δ = 3.3 ppm, s, 3H) of methoxy polyethylene glycol were confirmed. Accordingly, it was confirmed that the derivat ive having methoxy polyethylene glycol and N-acetylphytosphingosine coupled was synthesized.

<55>

<56> <Examples 1 to 6: manufacture of cream compositions>

<57> The inventors manufactured preferred embodiments of the invention as fol lows . The below examples 1 to 6 cream compositions contain different concentrations of N-acetylphytosphingosine-polyethylene glycol derivatives. Meanwhi le, a cream composition according to a comparat ive example as a negative control group for comparing with the Examples 1 to 6 was also manufactured. <58> [Table 1]

<59> <61> <60>

<67>

<68>

<69>

<70>

<71>

<72>

The inventors performed experiments for proving a whitening effect of sphingol ipid-polyethylene glycol of the invent ion as fol lows .

<73>

<74> <Experimental example 1: inhibit ing effects of sphingol ipid- polyethylene glycol derivatives on the melanin product ion>

<75> Melanin product ion inhibi t ing effects of each of N- acetylphytosphingosine-polyethylene glycol derivat ive, N-acetylsphinganine- polyethylene glycol derivat ive, N-acetylsphingadiene-polyethylene glycol derivat ive, N-acetylphytosphingosine, N-acetylsphinganine, N- acetylsphingadiene and koj ic acid were measured. The above materials were dissolved in DMSO (Dimethyl sulfoxide) and then used. In addit ion, cel ls strains to be used in this example were prepared by culturing B16F10 Melanoma which is a cel l of skin cancer of mouse in DMEM (Dulbecco^' s Modi fied Eagle Medium) containing 10% FBS (Fetal bovine serum) and ant ibiot ics in a CO2 incubator suppl ied wi th an air containing 5% CO2, at 37°C .

<76> A method of measuring melanin content is as fol lows . B16F10 mouse melanoma cel ls were inoculated on 24-wel l mult i-plate with 2x 10 cel ls/wel l and cultured in 5% CO2 incubator for 24 hours . After pre-culturing, test materials were di luted in DMEM containing no serums , treated to the cel l according to the concentrat ions thereof and then cultured for 96 hours. After washing with PBS, 0.85 N KOH was added and dissolved with ultrasonic waves, and an absorbance was measured at 475 nm and thus an amount of melanin was measured. On one hand, eumelanin and pheomelanin were subject to a fractional quant itat ive analysis using a high speed chromatography and product ion percents for a control group were obtained. The results are shown in table 2. The resultant values are product ion percents of melanin and indicate product ion percents (%) for a non-treated group.

<77>

<78> [Table 2] <79>

As can be seen from the above result , the concentrat ion inhibit ing the melanin synthesis of about 90% in al l samples was about 100 μ M in the case of the Koj ic acid. To the contrary, sphingol ipid-polyethylene glycol derivat ive had a melanin synthesis inhibit ing effect of about 90% at 1O y M which is 1/10 compared to the koj ic acid. Although it is not described in this example, it was found that arbut in had an equal level of an inhibit ing effect at 10 t imes concentrat ion of the koj ic acid and at 100 t imes of the compound of the invent ion. Further , as can be seen from the table, the sphingol ipid-polyethylene glycol derivat ive had a melanin synthesis inhibit ing effect twice or more as much as the sphingol ipid.

<80> Meanwhi le, the inventors photographed that the cel l strains used in this experiment was col lected using a centri fugat ion. This is shown in Fig. 1. In Fig. 1, the color of the lower part indicates a degree of melanin synthesis . As shown in Fig. 1, it can be seen that N-acetylphytosphingosine- polyethylene glycol derivat ive inhibited the melanin synthesis and thus color of the cel l lump was not changed to a black. That is , since the color is more l ighter compared to the N-acetylphytosphingosine, it could be seen that the N-acetylphytosphingosine-polyethlene glycol derivat ive had a more excel lent effect of inhibit ing the melanin priduction.

<81 >

<82> <Experimental example 2: inhibiting effect of N-acetylsphingosine- polyethylene glycol derivatives on tyrosinase activity >

<83> The inventors performed an experiment in order to examine the effect of N-acetylphytosphingosine-polyethylene glycol derivatives on tyrosinase act ivity as fol lows.

<84> In this experiment , N-acetylphytosphingosine-polyethylene glycol derivative was dissolved in DMSO (Dimethyl sulfoxide) as in the experimental example 1. In addit ion, cel ls strains to be used in the invention were prepared by culturing B16F10 Melanoma which is a cel l of skin cancer of mouse in a CO₂ incubator suppl ied with an air containing 5% CO₂, at 37°C using DMEM

(Dulbecco' s Modi fied Eagle Medium) containing 10% FBS (Fetal bovine serum) and antibiotics. A method of measuring a tyrosinase activity inhibition is as fol lows. B16F10 mouse melanoma cel ls were inoculated on 96-we11 multi-plate

₄ with Ix 10 cel ls/wel l and cultured in 5% CO2 incubator for 24 hours. After

pre-culturing, test materials were di luted in DMEM containing no serums, treated to the cel l according to their concentrations and then cultured for 96 hours . Then, they were washed twice with PBS. 1% Triton- X-100/PBS was added to it . After dissolving with ultrasonic waves , 5 μ 1 of 10 mM L-Dopa previously prepared to be 37°C was added and reacted for 30 minutes at 37°C . Then, an absorbancy was measured at 475 nm. The results are shown in Fig. 3. The resultant values are tyrosinase activities and indicate activity (%) for a non-treated group. Fig. 2 shows a standard curve of tyrosinase. <85> As can be seen from Fig. 3, it could be seen that N- acetylphytosphingosine-polyethylene glycol derivat ives had an effect of inhibiting about 50% of tyrosinase enzyme activity at about 10 μ M. Equal ly to the results of the experiment of melanin synthesis, this showed that N- acetylphytosphingosine-polyethylene glycol derivatives having concentrations of 1/10 of koj ic acid and 1/100 of arbutin had an outstandingly excel lent inhibitory effect , compared to the arbutin or koj ic acid.

<86>

<87> <Experimental example 3: whitening effect of cream composition of the invention on the human skin>

<88> The inventors performed this experiment to examine whether the composition of the invention actual ly exhibits a whitening effect on the human skin. It was measured whitening effects of the cream composit ions of the examples 1 to 6, and a whitening effect of the comparative example 1 was also measured to compare with the effects.

<89> For 20 healthy male persons, opaque tape having 1.5 cm diameter of perforation was stuck to the region of the arm of each of the examinees. Then, UVB having 1.5 to 2 times of minimal erythema dose of each examinee was appl ied to induce blackening of the skin. After that , the cream compositions of the examples 1 to 6 and the cream composition of the comparative example 1 were respectively appl ied, and l ight and darkness of the skin was measured using a spectrophotometer after two months. Each of test materials was appl ied two times every day at morning and evening.

<90> The effects were judged by calculat ing a L value indicating the l ight and darkness of the skin. <91> Δ L = L value on a last day at which the test material was appl ied -L value before applying the test material .

<92> The results are shown in table 3. <93> <94> [Table 3] <95>

<96>

<97> As can be seen from the results, it could be confirmed that the sphingol ipid-polyethylene glycol derivatives of the invention exhibited very excel lent whitening effects according to its concentration.

[Industrial Appl icabi l ity]

<98> As described above, the sphingol ipid-polyethylene glycol derivatives of the invent ion inhibit the melanin synthesis by suppressing the tyrosinase act ivity, thereby preventing and treating skin pigmentary symptoms such as melasma, ephel is, seni le pigment spot , and skin hyperpigmentation, etc.

Claims

[CLAIMS] [Claim 1]

<100> A sphingol ipid-polyethylene glycol derivative formed by combining sphingol ipid selected from a group consisting of N-acetylphytosphingosine, N- acetylsphinganine and N-acetylsphingadiene with polyethylene glycol . [Claim 2]

<101> The sphingol ipid-polyethylene glycol derivative according to claim 1, wherein the derivative is one of compounds having fol lowing formulas 1 to 3.

<102> [Chemistry Figure 1]

<104>

<105> [Chemistry Figure 2]

<107> [Chemistry Figure 3]

<109>

<110> , wherein Ri is independently hydrogen, alkyl group of Cw₀, alkenyl group of Ci-40, alkynyl group, acyl group or aryl group of Ci-40,

<111> when R₁ is acyl group

(COR2) , R2 is alkyl group, alkenyl group, alkynyl o

group or aryl group, <ii2> and X is -NR3-, -0-, -S- or -Xi-alk-X2-, wherein R3 is hydrogen, alkyl group, acyl group or aryl group of Ci-6, X₁ and X2 are independent ly amino group, amido group, carboxy group, cabamate group, carbony1 group, urea or phosphor0-, and aIk is alkylene of C₁^.

[Claim 3]

The sphingol ipid-polyethylene glycol derivat ive according to claim 2, wherein the polyethylene glycol has a molecular weight of 550 ~ 10,000Da.

[Claim 4]

<ii4> The sphingol ipid-polyethylene glycol derivat ive according to claim 3, which has polyethylene glycol having a molecular weight of 700 ~ 5,000Da and an end having a methoxy replaced.

[Claim 5]

<ii5> A composit ion for skin external use containing the sphingol ipid- polyethylene glycol derivat ive according to any one of claims 1 to 4 as an effect ive ingredient .

[Claim 6]

The composi t ion according to claim 5, wherein the composit ion suppresses a tyrosinase act ivity.

[Claim 7]

The composit ion according to claim 5, wherein the composit ion is a skin whitening composit ion.

[Claim 8]

<ii8> The composit ion according to claim 5, wherein the composit ion is a cosmet ics composit ion.

[Claim 9]

The composit ion according to claim 5, wherein the composit ion contains 0.005 ~ 10 wt .% of the sphingolipid-polyethylene glycol .

[Claim 10] <i2o> A method of suppressing a tyrosinase activity using the sphingolipid- polyethylene glycol derivative according to any one of claims 1 to 4.

[Claim 11]

<i2i> A method of suppressing a melanin synthesis using the sphingol ipid- polyethylene glycol derivative according to any one of claims 1 to 4.