WO2007105854A1

WO2007105854A1 - Novel lipoic acid conjugated compounds and skin external applications containing thereof

Info

Publication number: WO2007105854A1
Application number: PCT/KR2006/004465
Authority: WO
Inventors: Jin-Hwa Kim; Young Na; Bum-Chun Lee; Jun-Tae Bae; Gwan-Sub Sim; Hyeong-Bae Pyo
Original assignee: Han-Bul Cosmetics Co., Ltd.
Priority date: 2006-03-10
Filing date: 2006-10-31
Publication date: 2007-09-20
Also published as: JP2009510211A; JP4808781B2; KR100740071B1

Abstract

The present invention relates to derivatives of lipoic acid and skin external applications containing thereof that represent whitening effect, soothing effect, anti-aging effect and acne- improving effect and preventing effects of bladness disorder and seborrheic skin disorder.

Description

[DESCRIPTION] [Invention Title]

NOVEL LIPOIC ACID CONJUGATED COMPOUNDS AND SKIN EXTERNAL APPLICATIONS CONTAINING THEREOF [Technical Field]

<i> The present invention relates to lipoic acid used for anti-oxidant , whitening and anti-aging, more particularly novel water-soluble high molecule-lipoic acid conjugate in which a lipoic acid is conjugated with chemically water-soluble high molecule or a macromolecular carrier. And, the present invention relates to skin external composition containing lipoic acid-polyethylene glycol conjugate as a major active component, and this skin external composition is used for anti-oxidant, ant i-aging, ant i-wrinkle, whitening, relaxing skin stimuli, improving and preventing acne, improving dandruff and itching, and promoting hair growth. [Background Art]

<2> Human skin has experienced a lot of physical and chemical changes in aging process. Factors of aging are classified to intrinsic aging and photo- aging. A lot of scientists are studying factors of aging. Free radicals are activated with UV, stresses, sickness, environmental factors, injuries and aging, and if these conditions go bad, anti-oxidant defense networks in body are destroyed, cells and tissues are damaged, and as results aging is accelerated. In detail, lipids, proteins, polysaccharides and nucleic acids as skin constituents are oxidized, and therefore skin cells and skin tissues are damaged, and skin aging is occurred in the end. In particularly, reactive oxygen species formed from oxidation reactions damage collagen, hyaluronic acid, elastin, proteoglycan and fibronectin that are constituents of skin connective tissues, so the skin is inflamed, and elasticity of the skin is reduced. If a condition becomes worse, mutation and carcinogenesis are occurred, and immunity is reduced caused by DNA mutations.

<3> Therefore, free radicals produced during metabolism in body, by UV irradiation or inflammation should be removed in order to protect cell membrane, and already damaged cells should be regenerated and proliferated in order to recover healthy skin. Not only free radicals but also enzymes called matrix metal loproteases(MMPs) are concerned in aging. Synthesis and degradation of extra cellular matrix like collagen are controlled properly in body, but synthesis is reduced and matrix metal loproteases enzymes that break down collagens are activated as the process of aging. Therefore, elasticity of the skin is reduced and wrinkles are formed. These degradation enzymes are activated by irradiation of UV. Now, it is required to develop materials regulating expression of MMPs or inhibiting the activity of MMPs. Until now, most of materials of cosmetics are only inhibit the activity of MMPs. So, the present invention would provide materials not only inhibiting the activity of MMPs but also regulating expression of MMPs.

<4> Old-age society is coming due to developments of medical science and science. A concern about aging is increased, and baldness as a kind of aging state is increased exponentially. A concern about baldness extends to not only the elderly but also the younger generation and women. Therefore, effective novel material that promotes hair growth is needed desparately. A glossy skin due to exceeding secretion of sebum is called seborrheic symptoms that are usually appeared with a bald simultaneously. The seborrheic symptoms produced dandruff and proceed to chronic seborrheic dermatitis.

<5> 5- α-reductase closely relates to male hormone testosteron. It is known that testosteron is converted into dehydrotestosteron by 5- α-reductase in sebaceous glands of skin cell or head, and the dehydrotestosteron promotes sebum secretion. And, dehydrotestosteron is moved into hair papilla through blood, reduces adenyl cyclase activity in hair matrix, the hair follicle becomes atrophied, hair becomes thinner, at last get bald. Recently, developments of sebum secretion inhibiting reagent, dandruff inhibiting reagent and hair promoting reagent using inhibitor of 5- α-reductase are performed vigorously.

<6> Another concern is about skin darkness caused by pigmentation. Pigments which affects skin color are melanin, melanoid, carotene, hemoglobin etc., and the most important pigment is melanin. The most important factors of melanogenesis are UV irradiation and a secretion amount of hormones in body. Melanin prevents skin damage by absorbing or scattering UV, and absorb all area of light. Melanogenesis begins as an amino acid tyrosine converts dihydroxyphenylalanine by tyrosinase in melanosome of melanocyte. And then through a series of oxidation, polymers of phenomelanin and eumelanin are produced. The said biosyntheses process is performed in brown-colored melanosome, and melanosome containing melanin granule moves to dendrite, and then moved into cytoplasm by phagocytosis of keratinocyte, and accumulated around nucleus of the keratinocyte. Already, ascorbic acid(Japan patent publication H04-9320), hydroquinone(Japan patent publication H06-192062), kojic aciddapan patent publication S56-7710), arbutinUapan patent publication H04-93150) and a lot of natural plant extract are used as whitening cosmetics, but the problem of stablility, bad smell and ambiguous effect limit the uses.

<7> In order to dissolve the said problems, derivatives of a lot of chemicals are developed to improve the stability, solubility, absorption and cytotoxicity.

<8> So, the present inventors identified that if a soluble biodegradable macromolecule polyethyleneglycol and a lipoic acid were conjugated, the reformed lipoic acid shows improved solubility, stability, absorption rate , cytotoxicity, excellent anti-oxidant effect, whitening effect, anti-aging effect and soothing effect.

<9> Generally, soluble polymer region of derivatives is characterized to nontoxic, biocompatible, and typically from 2 to 300 termini. The said polymer is exemplified with polyethyleneglycol (PEG), polypropyleneglycol(PPG), polyoxyethylated polyol, polyolefin alcohol, but it is not restricted to the said polymers.

<io> Water-soluble polyethyleneglycol has a basic structure of HO- (CH2CH2θ)nCH2CH2-OH, and is used for foods or cosmetics. The polyethyleneglycol shows an effect to delay digestion of active material, so it is used for prescription of medicine. Polyethyleneglycol is a non-toxic macromolecule to human body, shows no antigenicity and is easily broken down in human body(Milos Dedlak, Collcet. Czech. Chem. Commun. , 70:260-290, 2005).

<ii> A conjugation reaction of active material by polyethyleneglycol (PEG) is called "PEGylation" and the product is called "polyethyleneglycol conjugate". By the reaction, the stability of the active material is improved, and the half-life period of the material becomes longer, therefore, using a less amount of the active material reduces cytotoxicity and is economic. In another aspect, it is advantageous to improving the insolubility of the active material, to reduce cytotoxicity caused by high concentraion of the active materiaKClaudia Furijteier-Polloth, Toxicology, 214:1-38, 2005, Robert A. Scott et al . , Biomaterials. , 20(15) : 1371-1380, 1999, R. B. Greenwald, J. contr 74:159-171, PEG drugs: an overview, WO 2003/037385). It is reported that a polyethyleneglycol by itself has no effect to eliminate free radicals and to inhibit xanthine oxidase, but a polyethyleneglycol could inhibit the generation of reactive oxygen and peroxidization of lipid by protecting damaged cell membrane(Jian Luo, et al . , J. Neurochem. , 83:471-480, 2002).

<i2> A conjugation method of active material by polyethyleneglycol is to activate a functional site by coupling reagent, and to dehydrogenate in the funtional group such as -NH₂, ~0H, -COOH or -SH. The conjugate is designed to be hydrolizable such as an ester, a thioester or an amide bond(Samuel Zalipsky, Advanced Drug Delivery Reviews , 16: 57-182, 1995).

<13> Lipoic acids are coenzymes in various plants and animals, and participates enzyme reactions in mitochondria. Octanoate is a precursor of C- 8 fatty acid chain of the lipoic acid, and a cystein is the source of sulfur. So, a biosynthesis of the lipoic acid is performed. Lipoic acids and their reduced form DHLA(dihydrolipoic acid) are known to be ant i-oxidant(Suzuki Y. T. et al., Free Rad. Res. Commun. 15:255-263, 1991, Scott B. C, et al . , Free Rad. Res. Commun. 20:119-133, 1994), and protect vitamine C and E(Likkesfeldt, J., et al., FASEB J. 12:1183-1189, 1998, Kagen, V. E., Serbinova, E. A., Forte, et al., J. Lipid Res. 33:385-397, 1992), protect and stimulate biosynthesis of gluthathion(Han D, et al., Biofactors 6:321-338, 1997, Sen CK, et al., Free Rad. Biol. Med. 22:1241-1257,1997), and become more effective by metal chelationCGregus Z, et al., Toxicol. Appl. Pharmacol. 114:88-96, 1992, Ou P, et al . , Biochem. Pharmacol. 50:123-126, 1995). The lipoic acid reduces tissue damages by UV irradiation by inhibiting NF~kB, and stimulates enzymes which only degradate damaged collagen fibers. And It is known that the lipoic acid controls the expression of microphthalmia- associated transcription factor and melanogenesis by inhibiting the activity of tyrosinase(Lin CB, et al., J. Invest. Dermatol. 119(6) :1330-1340, 2002).

<i4> However, a cosmetic or drug formulation of a lipoic acid is difficult because of water-insolubility of the lipoic acid. And, it is known that the lipoic acid contains reactive sulfhydryl group, so easily oxidized to disulfide, and get worse in water solubility, color and smell, and more easily degradated. It is proposed that mixing vitamine C, vitamine E and the thio-compound could offer more stable composition(A. Segal 1, et al., J. Cosmet. Sci., 55:419-461, 2004,EP0349797Bl, Japan patent publication S53- 7488).

<i5> But, there are many restrictions for improving the stability of lipoic acid in this way, and smell, stability of the formulation and effects are falling down. As cases of derivatives of lipoic acid, a cosmetic composition containing lipoic acid conjugated with vitamin C, vitamin E or flabonoid(W02005072505), a whitening cosmetic composition containing lipoic acid conjugated with α-MSH(W095/08564), diabetes treatment composition containing lipoic acid derivative in which a thiol site is conjugated with fatty acid(EP0317264) etc., a report that lipoic acid conjugated to indole is improved in inhibiting hyperoxidation of lipidCGurkan AS, et al . , Arch. Pharm. (Weinheim), 338(2-3):67-73, 2005), diabetes treatment composition containing lipoic acid conjugated with hydrosuccinimide(Gruzman A, et al . , Bioorg. Med. Chem. Let., 12(5): 1183-1190, 2004) and conjugation with NOS(nitric oxide synthase)(Harnett JJ, et al., Bioorg. Med. Chem. Let., 12(11): 1439-1442, 2002) etc. were published. A case was reported that polyethyleneglycol conjugate of lipoic acid, but the conjugate was not prepared to a specific purpose but only to use as a control(Gruzman A, et al., Bioorg. Med. Chem. Let., 12(5): 1183-1190, 2004, Bruggraber SF, et al . , Gastroenterology, 125(6): 1705-1713, 2003). Former researches about derivative of lipoic acid were not published lipoic acid-polyethyleneglycol conjugate improved in solubility, cytotoxicity and stability as a cosmetic material. [Disclosure] [Technical Problem]

<16> It is an object of the present invention to provide a water-soluble derivative of lipoic acid, and to examine the effect thereof as a raw material of skin external composition, and to provide a producing method of funtional skin external compositions containing thereof.

<i7> In detail, it is an object of the present invention to develop a material that represent anti-oxidant effect, anti-wrinkle effect, whitening effect, anti-aging effect, relaxing skin stimuli, improving acne, preventing acne, improving dandruff and itching, promoting hair growth, and to provide cosmetics containing the material.

<i8> And, it is an object of the present invention to provide a novel soluble derivative of lipoic acid that is easy for formulation, processing and delivery in compare with non-reformed lipoic acid.

<i9> And, it is an object of the present invention to provide a novel derivative of lipoic acid which is improved in stability against acid, high temperature and UV, absorption rate in epidermis and cytotoxicity in compare with non-reformed lipoic acid.

<20> And, it is other object of the present invention to provide a cosmetic composition containing soluble derivative of the lipoic acid. [Technical Solution]

<2i> In order to achieve these objects, the present invention provides water-soluble lipoic acid-polyethyleneglycol conjugate of chemistry figure 1 that lipoic acid is chemically bound to a soluble carrier. <22> [Chemi stry Figure 1]

<23> wherein: X is a hetero atom selected from the group consisting of O, N- H and S; n is a fixed number of 4-2,000; R is a functional group selected from the group consisting of -H, alkoxy, benzyloxy, hydroxyl , active ester, active carbonate, acetal, aldehyde, aldehyde hydrate, alkenyl, acrylate, metacrylate, acrylamide, active sulfone, amine, hydrazide, thiol, carboxylate, lipoate, isocyanate, isothiocyanate, maleimide, vinylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, glyoxal, dione, mesylate, tosylate, tresylate, and the functional equivalent thereof.

<24> In a desirable embodiment, a derivative of the present invention contains hydrolyzable bond such as an ester bond between lipoic acid and polyethylene glycol. Therefore, in the said example, the lipoic acid- polyethylene glycol derivative is thought to be a precursor, and it means that if the hydrolyzable bond is cut off, non-reformed lipoic acid would be produced.

<25> The n of polyethyleneglycol part is 4-2,000, and the molecular weight is 200-100,000dalton. The R is -H or terminal capping group such as alkoxy or benzyloxy, or reactive functional group such as hydroxyl, active ester, active carbonate, acetal, aldehyde, aldehyde hydrate, alkenyl, acrylate, metacrylate, acrylamide, active sulfone, amine, hydrazide, thiol, carboxylate, lipoate, isocyanate, isothiocyanate, maleimide, vinylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, glyoxal, dione, mesylate, tosylate, tresylate, and the functional equivalent thereof. The said funtional equivalent means derivative of functional group such as an alkoxy group etc. which does not affect the properties of material as shown in the formula 1. <26> The polyethyleneglycol which is used to form the derivative of the present invention could have any geometric structure containing linear, branched, porked or dumbbell-shaped.

<27> The present invention provides a lipoic acid derivative which has hydrolyzable linkage containing soluble conjugate covalently bonded to carbonyl carbon of the lipoic acid. A desirable linkage contains an ester bond, a thioester bond and an amide bond, and the linkage is made using the usual coupling method in the present technical field. Lipoic acid- polyethyleneglycol conjugate could be formed if activated soluble derivative be reacted with carboxylate group, reactive carboxylate, a functional group reactive with halide acid such as hydroxyl group or thiol group. As described in embodiment, the coupling reaction is performed by adding coupling agent 1- ethyl-3-(3'-dimethylaminoproρyl)carboimide and N.N'-dimethylaminopyridine.

<28> And, the lipoic acid derivative composition of the present invention is soluble in water, so detergent and organic solvent are not necessary, and a large amount of the lipoic acid derivative could be contained in composition.

<29> And, the present invention provides skin external composition containing the soluble lipoic acid derivative as an effective ingradient.

<30> And, the skin external composition of the present invention is characterized to contain in an amount of 0.001-30wt% of the lipoic acid- polyethyleneglycol conjugate. If the amount of the compound is less than 0.001wt% of the total composition cannot be expected, while if the amount of the compound exceeds 30wt%, it is not economic.

<3i> The present invention is characterized that the said skin external composition is selected from the group comprising cosmetic solution, gel, soluble liquid, cream, essence, pack, oil-in-water type formulation, water- in-oil type formulation, powder, ointment, hair tonic, hair lotion, hair cream, shampoo and rinse. [Advantageous Effects]

<32> As explained above, the lipoic acid-polyethyleneglycol conjugate represented excellent anti-aging effects such as antioxidant effect and matrix metal loprotease inhibition effect.

<33> And, the lipoic acid-polyethyleneglycol conjugate represented whitening effect such as melanogenesis inhibition effect and tyrosinase inhibition effect.

<34> And, the lipoic acid-polyethyleneglycol conjugate represented acne preventing effect by inhibiting the growth of acne bacteria and inhibiting sebum secretion by inhibiting 5- α-reductase.

<35> And, the lipoic acid-polyethyleneglycol conjugate was identified to be more stable in acidic, hot or UV-irradiated condition compared with non- reformed lipoic acid.

<36> And, the lipoic acid-polyethyleneglycol conjugate was identified to be more soluble in water compared with non-reformed lipoic acid.

<37> And, the lipoic acid-polyethyleneglycol conjugate was identified to be less cytotoxic compared with non-reformed lipoic acid.

<38> And, the lipoic acid-polyethyleneglycol conjugate was identified to represent improved absorption rate in epidermis compared with non-reformed lipoic acid.

<39> And, the lipoic acid-polyethyleneglycol conjugate was identified to represent improving dandruff and itching, and hair promoting effect.

<40> Therefore, cosmetic composition containing the lipoic acid- polyethyleneglycol conjugate such as cosmetic solution, cream, emulsion, pack, powder, ointment, hair tonic, hair lotion, hair cream, shampoo and rinse represents excellent effects such as antioxidant effect, controlling effect of collagenase activity, whitening effect, soothing effect, improving dandruff and itching, and promoting hair growth as skin external applications. The said composition is stable to acidic, hot or UV-irradiated condition, and represents low cytotoxicity. So, it is possible to contain high concentration of lipoic acid in the said composition. And, the said composition is favorable for formulation. [Description of Drawings]

<4i> Fig. 1 shows a graph high performance liquid chromatography test result of cream formulation containing non-reformed lipoic acid before and after 6 months storage in room temperature.

<42> Fig. 2 shows a graph high performance liquid chromatography test result of cream formulation containing the lipoic acid-polyethylene glycol conjugate before and after 6 months storage in room temperature.

[Best Mode]

<43> Preparation of lipoic acid-polvethyleneglycoKlkDa) conjugate <44> In flask, 250mg of methoxypolyethyleneglycoKM.W. 1000), 58mg of lipoic acid, 52.7mg EDCI and as a catalyst a little amount of DMAP were stirred for 3 hours in dark condition. The solvent of reaction mixture was removed by vacuum distillation, and dried residues were dissolved to a little amount of dichloromethane, and diethylether was added to it. Precipitate was collected by filter, washed by ether, dried in vacuum. The purity of product was identified using C18 column high performance liquid chromatography eluted by H₂O: acetonitrile gradient. The compound was pale yellow crystal, and the yield was at least 95%.

<45> Preparation of _a cosmetic solution containing the lipoic acid- polvethyleneglycol conjugate

<46> 8g of 95% ethanol, 0.05g of polypyrolidon, O.lg of oleylalcohol , 0.2g of polyoxyethylenemonooleate, 0.2g of perfume, O.lg of polyoxyethylenesorbitanemonooleate, a little amount of anti-oxidant , a little amount of pigment were mixed and dissolved. 0.05g of lipoic acid- polyethyleneglycol conjugate prepared above described, 5g of glycerin were dissolved in 85.33g of purified water, and the said mixture was added to provide a cosmetic solution with skin improving effect. [Mode for Invention]

<47> The present invention will be explained in more detail with reference to the following embodiments. However, it is to be noted that the present invention can be utilized in various ways and it is not intended to be confined to the embodiments.

<48> Embodiment l: preparation of lipoic acid-polyethyleneglycol(2kPa) conjugate

<49> In flask, 500mg of methoxypolyethyleneglycoKM.W. 2000), 58mg of lipoic acid, 52.7mg of EDCI(l-ethyl-3-(3 '-dimethylaminopropyDcarboimide) and as a catalyst a little amount of DMAP(N,N'-dimethylaminopyridine) were stirred for 3 hours in dark condition. The solvent of reaction mixture was removed by vacuum distillation, and dried residues were dissolved to a little amount of dichloromathane, and diethyleter was added to it. Precipitate was collected by filter, washed by ether, dried in vacuum. The purity of product was identified using C18 column high performance liquid chromatography eluted by H₂O: acetonitrile gradient. The compound was pale yellow crystal, and the yield was at least 92%.

<50> Embodiment 2: preparation of lipoic acid-polyethyleneglycol(IkDa) conjugate

<5i> In flask, 250mg of methoxypolyethyleneglycoKM.W. 1000), 58mg of lipoic acid, 52.7mg EDCI and as a catalyst a little amount of DMAP were stirred for 3 hours in dark condition. The solvent of reaction mixture was removed by vacuum distillation, and dried residues were dissolved to a little amount of dichloromathane, and diethyleter was added to it. Precipitate was collected by filter, washed by ether, dried in vacuum. The purity of product was identified using C18 column high performance liquid chromatography eluted by H₂O: acetonitrile gradient. The compound was pale yellow crystal, and the yield was at least 95%.

<52> Embodiment _3_1 preparation of lipoic acid-Polvethyleneglycol(500Da) conjugate

<53> In flask, 120mg of methoxypolyethyleneglycoKM.W. 500), 58mg of lipoic acid, 52.7mg EDCI and as a catalyst a little amount of DMAP were stirred for 3 hours in dark condition. The solvent of reaction mixture was removed by vacuum distillation, and dried residues were dissolved to a little amount of dichloromathane, and diethyleter was added to it. Precipitate was collected by filter, washed by ether, dried in vacuum. The purity of product was identified using C18 column high performance liquid chromatography eluted by H2O: acetonitrile gradient. The compound was pale yellow crystal, and the yield was at least 94%.

<54> Embodiment 4: dissolving test <55> The lipoic acid-polyethyleneglycol conjugates of the embodiments 1-3 were dissolved in lm£ of distilled water, respectively. Dissolving rates of the lipoic acid-polyethyleneglycol conjugate were measured by Haxemeter(NHD- 300A, Nippon denshocku IND). The sample's amount revealed at most 0.5 by Haxemeter, and the solubility of the sample was determined in liquid state. The result was shown in Table 1.

<56> [Table 1]

<57> <58> Embodiment 5: cvtotoxycitv test <59> In the present embodiment, the cytotoxicity of lipoic acid- polyethyleneglycol conjugates obtained from embodiments 1-3 were tested, and then compared to that of non-reformed lipoic acid. Fibroblasts were aliquoted

5 1x10 into each well of 24-well microtiter plate, and attached for 24 hours.

Then, lipoic acid-polyethylene glycol derivatives and a non-reformed lipoic acid to be tested were added into it, and were cultured. After 24 hours culture, the media was taken out, and 500μ£ of cell culture media and 60μi of MTT solution(2.5mg/m£) were added to each well, and were cultured for 2 hours at 37°C in CO₂ condition. After removing out the media, 500μC of isopropanol-

HCl(0.04N) was added. After dissolving the cells by 5 minutes' shaking, lOOμβ of the supernatent were aliquoted into 96-well microtiter plate, and absorbance at 565nm was measured. Cell viabi lity(%) was determined in the following math figure 1. <60> [Math Figure 1]

CeU viability (%)= [(St-Bo)/(Bt-Bo)]x 100

<61> Bo: Absorbance of the well in which fibroblast and sample were not added at 565nm

<62> Bt: Absorbance of the well in which sample is not added at 565nm <63> St: Absorbance of the well in which sample is added at 565nm <64> In the result, 5mM of lipoic acid-polyethylene glycol derivatives relieved 10-20% of cytotoxicity compared to non-reformed lipoic acid(Table

2).

<65> [Table 2]

<66> Embodiment 6: Anti-oxidant test by DPPH method <67> In the present embodiment, anti-oxidant activity of lipoic acid- polyethyleneglycol conjugates(embodiments 1~3) were tested using DPPH method, and then compared to those of non-reformed lipoic acid and ascorbic acid in laboratory condition.

<68> In DPPH method, 2,2-Di(4-tert-octylphenyl)-l-picrylhydrazyl free radical(DPPH) was used to test anti-oxidant activity of samples. DPPH was reduced by samples, and the absorbance at 560nm was reduced. The extent of absorbance reduction was compared to that of blank, and then free radical elimination rate was determined.

<69> As a reagent, DPPH{2,2-Di(4-tert-octylphenyl)-l-picrylhydrazyl free radicalKAldrich Chem. Co., M.W.=618.76) O. ImM solution was used, made by dissolving 61.88mg of DPPH to MeOH and set to final vol. 100m*.

<70> A measuring method is followed. <7i> φ 0.15m£ of O.lmM DPPH solution and 0.15m£ of a sample solution are added to 96-well plate, and stirred immediately, which are maintained at 25^°C for lOmin.

<72> Φ Then, absorbance of Sample(St) at 560nm is measured. <73> <3) Blank test is carried out in the same way except distilled water is used instead of sample solution and absorbance of Blank(Bt)is measured. <74> © And, blank test for sample is carried out in the same way except distilled water is used O.lmM DPPH solution and absorbance(Bo) is measured. <75> The effect was calculated in the following way. The result is shown in

Table 3. <76> [Math Figure 2]

Inhibition rate(%)=[l- (St-So)Z(Bt-Bo)] x 100

<77> St: absorbance of sample solution at 560nm after free radical elimination <78> Bt: absorbance of blank test solution at 560nm after free radical elimination <79> So-' absorbance of sample solution at 560nm before reaction without free radical addition <80> Bo: absorbance of blank test solution at 560nm before reaction without free radical addition <8i> As shown in the table 3, lipoic acid-polyethyleneglycol conjugates(embodiment 1-3) showed more excellent effect in active oxygen elimination in 5OmM concentration. But, samples of embodiments 1~3 were not effective than ascorbic acid. <82> [Table 3]

<83> Embodiment T- tyrosinase inhibition test

<84> Tyrosinase inhibition effect of lipoic acid-polyethyleneglycol conjugates of embodiment 1, 2, 3, kojic acid, and non-1 iformed lipoic acid as controls were measured in lab conditions.

<85> Tyrosinase is an enzyme accelerating first oxidation process in which tyrosine is oxidized to dopa and second oxidation process in which dopa is oxidized to dopaquinone. Tyrosinase activities were inhibited by samples, and it was determined by measuring absorbance at 490nm compared to that of blank.

<86> 15μJt of each sample, 150μJt of 5OmM phosphate buffer(pH 6.5) and 25/.I of 1.5mM L-tyrosine solution was put into 96 well microtiter plate, after that 10μ(5 of mushroom tyrosinase(l,500units/m£, Sigma) was added, and reacted at 37^°C for 20min. Absorbance in 490nm was measured using the microplate reader(ELx800, U.S.). The tyrosinase inhibition rate(%) was calculated in the following way. The result is shown in Table 4.

<87> [Math Figure 3]

Inhibition rate(%)= [(D-C)- (B-A)/(D-C)]x 1OO

<88> A: the zero cycle absorbance of the well in which a sample was added

<89> B: an absorbance after the reaction of the well in which a sample was added

<90> C: the zero cycle absorbance of the well in which a sample was not added

<9i> D: an absorbance after the reaction of the well in which a sample was not added

<92> As shown in Table 4, lipoic acid-polyethyleneglycol conjugates(embodiment 1~3) revealed at least 30% higher tyrosinase inhibition effect at 2.5mM concentration than non-reformed lipoic acid. But, samples of embodiments 1-3 were not effective than kojic acid.

<93> [Table 4]

<94> Embodiment 8: Paper disk test <95> In the present embodiment, paper disk test for identifying anti^¬ bacterial effect against acne bacteria of embodiment 1-3 and non-reformed lipoic acid. AT first, Propionibacterium acnes were precultured for 48 hours in BHI liquid medium(Brain-Heart Infusion Broth; 3.7wt%). Cultured media prepared by the said way were spreaded to 3.7wt% of Brain-Heart Infusion Broth containing 1.5wt% of agar and then dried. Lipoic acid- polyethyleneglycol conjugates(embodiment 1-3) and non-reformed lipoic acid were diluted in 95% of ethanol to 12w/v% and 50μi of the said samples were aliquoted into δmm-diameter paper disc, respectively. The paper discs were set onto the said bacteria-cultured solid media, and cultured for 3 days at 35^°C . The antibacterial activity was determined by measuring a diameter of growth inhibition zone.

<96> In the result shown as Table 5, a diameter of growth inhibition zone of lipoic acid-polyethyleneglycol conjugates(embodiment 1~3) was about 30mm and that of non-reformed lipoic acid was about 22mm. The antibacterial activity of lipoic acid-polyethyleneglycol conjugate was superior to non-reformed lipoic acid.

<97> [Table 5]

<98> Embodiment 9: 5- α-reductase inhibition test

<99> In the present embodiment, 5- α-reductase inhibition effect of lipoic acid-polyethylene glycol derivative obtained in the embodiment 1 was tested. <ioo> In this test, 5- α-reductase is an enzyme synthesized from foreskin fibroblast. Fibroblasts were aliquoted 100,000 cells per microplate hole and

3 cultured. O.lmμCi of H radio labelling testosterone was added to every hole and was cultured to identify if the cells use that or not. In a control, a lipoic acid-polyethyleneglycol conjugate or a non-reformed lipoic acid was not added. After 24 hours culture, ImI of ethyl acetate: cyclohexane(l:l) extraction solvent was added to supernatent and steroids were obtained. The steroids were chromatographed with chloroform/methanol{98/2(v/v)}. The radiodensities of testosterone corresponding spot and dihydrotestosterone corresponding spot were measured, and transforming rate was determined, and the result was compared to the control. And then, 5- α-reductase inhibition effect of sample was evaluated. <ioi> [Math Figure 4]

Inhibition rate(%)=[(A-B)/A]x 100

ϊi02> A: transforming rate from testosterone to dihydrotestosterone in blank ϊi03> B: transforming rate from testosterone to dihydrotestosterone in sample solution

=i04> In the result, the 5- α-reductase inhibition rate of lipoic acid- polyethyleneglycol conjugates(embodiments 1~3) were at least 75% at 1OmM concentration. And the result is 40% higher than that of non-reformed lipoic acidCTable 6). Therefore, lipoic acid-polyethyleneglycol conjugate is expected to inhibit secretion of sebum, to treat acne, to improve dandruff, and to promote hair growth effectively.

<105> [Table 6]

<106> Embodiment 10: matrix metal loprotease _1 inhibition test after UV irradiation

<107> In the present embodiment, enzyme-linked immunosorbant assay was performed to measure matrix metal loprotease l(MMP-l) comcentration after irradiating UV and adding lipoic acid-polyethyleneglycol conjugates samples in the embodiments 1-3.

<108> UVA was irradiated in the energy of 6.3J/cnf in the human fibroblast cell using UV chamber. Through a pilot study, UV dose and incubation time condition were established in order to maximize MMP-I expression in fibroblast. Negative control group was wrapped with a silver foil and it maintained for same time. UVA emission amount was measured by UV radiometer. The cell while UVA was irradiated was remained as it was with culture medium, and after irradiating UVA it was exchanged to culture medium in which a sample was added, and the cell was collected after 24 hours culture and it was previously coated on 96 well microtiter plate.

<109> Primary antibody!monoclonal antibody for MMP-KAb-5) and monoclonal antibody for MMP-2(Ab-3)} was added at 37°C for 60 minutes. After anti-mouse IgGCwhole mouse, alkaline phosphatase conjugated) as a secondary antibody was reacted to the well for 60 minutes, alkaline phosphatase substrate solutionQ mg/m£ p-nitrophenyl phosphate in diethanolamine buffer) was added at room temperature for 30 minutes, absorbance was measured in 405nm using photometer. In a control, a sample was not added.

<1 10> In results, lipoic acid-polyethyleneglycol conjugates(embodiments 1~3) inhibit at least 75% MMP-1 expression induced by UV irradiation compared to control. And the result is higher than that of non-reformed lipoic acid(Table 7). And, ono-reformed lipoic acid has no inhibition effect for MMP-I expression induced by UV irradiation.

<111> [Table 7]

<112> Embodiment 11: melanogenesis inhibition evaluation using melanocyte B16F1

<113> In the present embodiment, the whitening effect was determined according to the melanogenesis suppression rate about the B16F1 melanocyte in order to confirm the whitening effect of the lipoic acid-polyethyleneglycol conjugates in the embodiments 1~3.

<114> The B16F1 melanocyte used for this embodiment is the cell strain derived from a mouse, and it is the cell secreting the black pigment called melanin. A sample was added in the meantime of culturing the cell. And the melanin pigment reducing extent was comparatively evaluated. The B16F1 melanocyte used for this embodiment was acquired from ATCCCAmerican Type Culture Collection, accession number: 6323).

<115> The melanogenesis inhibition effect in the B16F1 melanocyte was performed as follows. Melanocyte B16F1 was aliquoted into 6 well microtiter

6 plate to 2x10 concentration per each well, and attaching the cell into the well, and cultured for 72 hours. A sample was added into the well as a concentration which did not induce toxicity. After 72 hr culturing, cells were removed using trypsin-EDTA, and the cell number was measured. And then, the cells were collected by centrifugation. A measuring of quantity for melanin within the cell was performed by modified Lotan's method(Lotan: cancer Res., 40: 3345-3350, 1980). After washing the cell pellet by PBS 1 time, homogenization buffer solution(50mM sodium phosphate, pH 6.8, 1% Triton X-IOO, 2mM PMSF) lm£ was added and it flowed in whirls for 5 minutes and cells were crushed. After dissolving the melanin adding IN Na0H(10% DMSO) in the cell lysate obtained by centrifugation(3,000rpm, 10 minutes), the absorbance of the melanin was measured in 405nm, and the quantity of melanin wea measured. And then, melanogenesis inhibition rate was determined. A me1anogenesis inhibition rate in B16F1 melanocyte was determined in the following math figure 5. The IC₅₀ value is the concentration of the material inhibiting melanogenesis by 50%.

<116> [Math Figure 5]

Inhibition rate(%)=[(A-B)/A]x 1OO

<117> A: melanin amount of the well in which the sample was not added <118> B: melanin amount of the well in which the sample was added <U9> In results of melanogenesis inhibition test in the B16F1 melanocyte, IC₅₀ values of lipoic acid-polyethyleneglycol conjugate(embodiments 1-3) were

0.5mM, and the values were the same of the ICs₀ value of non-reformed lipoic acid, and better than that of hydroquinone, arbutine known as whitening materialsCTable 8).

<120> [Table 8]

<121> Embodiment 12: cytotoxicity relieving test caused by UV irradiation <122> In the present embodiment, the cytotoxicity relieving effect of lipoic acid-polyethyleneglycol conjugates in the embodiments 1~3 caused by UV irradiation was tested. 5

<123> Fibroblast was aliquoted into 24 well microtiter plate to 1X10 concentration per each well, and attaching the cell into the well, and cultured for 24 hours. After each well was washed by PBS 1 time, 500μJl of PBS was added to each well. The fibroblasts were irradiated by 10mJ/cπf of UV using UVB lampCModel: F15T8, UVB 15W, Sankyo Dennki , Japan). And then, PBS buffer was taken out from the well, and ImI of cell culture mediaCfetal bovine serum is added to Dulbecco's Modified Eagle Medium) was added. And then, lipoic acid-polyethyleneglycol conjugates and non-reformed lipoic acid were added respectively, and cultured for 24 hours. After 24 hours, the media was taken out, and δOOμ€ of cell culture media and 60μl of MTT solution(2.5rag /mi) were added in order to culture for 2 hours at 37°C in CO₂. Afte taking out the media, 500μβ of isopropanol-HCl(0.04N) was added. After dissolving the cells by 5 minutes' shaking, lOOμi of supernatent were aliquoted into 96- well microtiter plate, and 565nm absorbance was measured. Cell viability was determined in the following math figure 6, and cytotoxicity relieving rate caused by UV irradiation was determined in the following math figure 7. i24> [Math Figure 6]

cell viability(%)=[(St-Bo)/(Bt-Bo)]x 100

125> Bo: absorbance of the well at 565nm in which there is a cell culture media i26> Bt-^' absorbance of the well in which a sample was not added I27> St: absorbance of the well at 565nm in which a sample was added I28> [Math Figure 7] cytotoxicity relieving rate(%)=[l-(St-Bo)/(Bt-Bo)]x 100

29> Bo: cell viability of the well in which a sample was not added, and UV was not irradiated 30> Bt: cell viability of the well in which a sample was not added, and UV was irradiated <131> St^ cell viability of the well in which a sample was added, and UV was irradiated

<132> In the result, lipoic acid-polyethyleneglycol conjugates(embodiments 1~3) relieved at least 30% of cytotoxycity caused by UV irradiation at 0.5mM concentration. And the result is 20% higher than that of non-reformed lipoic acicKTable 9).

<133> [Table 9]

<134> Embodiment 13: inhibition test for inflammatory cytokine expression caused by UV irradiation

<135> In the present embodiment, the inhibition effect for inflammatory cytokine expression caused by UV irradiation of lipoic acid- polyethyleneglycol conjugates in the embodiments 1-3 were tested. Fibroblasts

4 obtained from human epidermis were aliquoted 5X10 into each well of 24-well microtiter plate, and were attached for 24 hours. Each well was washed by PBS 1 time, and 500μ£ of PBS was added to each well. The fibroblasts were irradiated by 10mJ/cnf of UV using UVB lamp(Model: F15T8, UVB 15W, Sankyo Dennki , Japan). And then, PBS buffer was taken out from the well, and 350μi of cell culture media(fetal bovine serum is not added to Dulbecco's Modified Eagle Medium) was added. And then, lipoic acid-polyethyleneglycol conjugates were added, and cultured for 5 hours. Prostaglandin E₂ in 150μJt of supernatent was measured, and the inhibition effect for inflammatory cytokine expression of lipoic acid-polyethyleneglycol conjugates were tested. The amount of Prostaglandin E₂(PGE₂) was measured by Emzyme-1 inked immunosorbant assay. The

PGE₂ producing rate was determined in the following math figure 8. <136> [Math Figure 8]

FGE₂ expression inhibition rate<%)=[l-(St-Bo)/(Bt-Bo)]χ 100

<137> Bo: PGE2 amount of the well in which a sample was not added, and UV was not irradiated

<138> Bt: PGE2 amount of the well in which a sample was not added, and UV was irradiated

<139> St: PGE₂ amount of the well in which a sample was added, and UV was irradiated

<140> In the result, lipoic acid-polyethyleneglycol conjugates(embodiments 1-3) inhibited at least 55% of inflammatory cytokine expression caused by UV irradiation at 0.25mM concentration. And the result is better than that of non-reformed lipoic acid(Table 10).

<141> [Table 10]

<142> Embodiment 14: stability test of lipoic acid-po1yethy1ene glycol derivatives

<143> In the present embodiment, solution and cosmetic containing lipoic acid-polyethyleneglycol conjugate(embodiment 1) of the present invention were tested in 2 different temperatures(room temperature, high temperature), 3 different pHs(acidic, neutral, alkaline), and 2 different light conditions(darkness, UV irradiation), and then compared to that of non- reformed lipoic acid. d44> A lipoic acid-polyethyleneglycol(2kDa) conjugate(embodiment 1) and a non-reformed lipoic acid were completely dissolved to 30% ethanol contained buffers(pH 4.0: acetate buffer, pH 7.0: phosphate buffer, pH 10.2: bicarbonate buffer) respectively. Cosmetics containing lipoic acid- polyethylene glycol derivative or non-reformed lipoic acid were cream formulations, and the formulations were shown in Table 11. At first, B mixture in Table 11 was heated and reserved at 70°C. To the said B mixture, A mixture was added and pre-emulsified, and homogeneously emulsified using homomixer, and then, cooled slowly to produce cream formulation.

<i45> The said creams and solutions were stored in room temperature(dark), high temperature(54°C , dark) and UV irradiationCroom temperature) conditions during 6 months, and then solubility and smell were observed and compared to those of immediately after preparation. Results were shown in Table 12. And, using analytical reversed-phase HPLC a quantity analysis was performed to identify the tability of major constituent. The result was shown in Table 13. The HPLC results after 6 months storage in room temperature were shown in Fig. Kcream formulation containing lipoic acid-polyethylene glycol conjugate) and Fig.2(cream formulation containing non-reformed lipoic acid).

<146> The HPLC analysis was performed using C18 analytical column(Xterra, 5um, 4.6X250mm, Waters). In the test of lipoic acid-polyethyleneglycol conjugate prepared by embodiment 1, mobile phase(40% of acetic acid, pH 4.5, and 60% of methanol) was applied, and was detected UV absorbance at 300nm. In the case of non-reformed lipoic acid, mobile phase(30% of acetic acid, pH 4.5, and 70% of methanol) was applied, and was detected UV absorbance at 330nm. ci47> [Table 11]

<148> <149> [Table 12]

<150> (-: not changed, *: bad smelled, I : precipitated) <151> <152> [Table 13]

<153> As shown in Table 12, non-reformed lipoic acid smelled bad in acidic, neutral and basic condition, and in cream formulation(* the formulation in Table 11) condition. Especially, at room temperature, high temperature and UV irradiation conditions in acidic pH, the non-reformed lipoic acid smelled worse. In case of lipoic acid-polyethyleneglycol conjugate, the smell was improved than that of non-reformed lipoic acid.

<154> In Table 13, after storage, the content of non-reformed lipoic acid in acidic and room temperature condition was 44%, in compare with 64% in neutral condition and 62% of basic condition. The non-reformed lipoic acid was less stable in acidic condition. And, the non-reformed lipoic acid content of cream formation in acidic condition was more reduced in compared with that in acidic solution. However, the lipoic acid-polyethyleneglycol conjugate was shown to be stable and less smelled compared to non-reformed lipoic acid.

<i55> Embodiment 15: hydrolysis of lipoic acid-polyethyleneglycol conjugate

<i56> Stabilities in various temperatures, chemical and enzymatic hydrolysis conditions of lipoic acid-polyethyleneglycol conjugate of the present invention were tested.

<i57> 0.5wt% of lipoic acid-polyethyleneglycol conjugate(embodiment 1~3) was dissolved in phosphate buffer(0.1M, pH 7.4) and reserved at 23°C and 37^°C respectively. And, lipoic acid-polyethyleneglycol conjugate(embodiment 1~3) was dissolved in phosphate buffer(0.1M, pH 7.4) containing porcine esterase and reserved at 37°C. Analytical reversed-phase HPLC was performed. The condition of HPLC was same in Embodiment 14.

<158> A half-life period was determined using pseudo-first-order kinetics. As shown in Table 14, in 23^°C buffer solution the half-life period of lipoic acid-polyethyleneglycol conjugate(embodiment 1~3) was about 3,000hr, but that in 37°C was 800hr. And, the half-life period of lipoic acid- polyethyleneglycol conjugate in buffer containing porcine esterase was as short as 5hr. In the results, we know that hydrolyzable property of the ester bond of the lipoic acid-polyethyleneglycol conjugate. The conjugate of the present invention is characterized to be a soluble precursor of lipoic acid.

<i59> [Table 14]

<160> <161> Embodiment 16: transdermal absorption increasing effect of lipoic acid- polyethyleneglvcol conjugate

<162> In the present embodiment, a cosmetic containing lipoic acid- polyethyleneglycol conjugate obtained from embodiment 1 was prepared and transdermal absorption test of the cosmetic was performed compared with that of a cosmetic containing non-reformed lipoic acid. Experimental animal was 8- week-old female guinea pigCstrain IAF/HA-hrBR) .

<163> An abdominal skin cut away from the guinea pig was transplanted to Franz-type diffusion cell(Lab Fine Instruments, Korea). The diffusion cell was mixed and diffused into a the Franz-type diffusion cell receptor vessel containing 5OmM of phosphate bufferCpH 7.4, 0.1M NaCl) at 32°C , in 600rpm. And then, 50μ£ of 10wt% diffused solution of the cosmetic prepared by Table 11 was added to doner vessel. At 37"C , absorption and diffusion was performed. After finished, remained emulsion was removed, the skin in which the effective material was absorbed and diffused was homogenized using tip- type homogenizer(Polytron PT2100, Switzerland). Lipoic acid- polyethyleneglycol conjugate and non-reformed lipoic acid were extracted by 4 ml of dichloromethanol , respectively. The exteact were filtered with 0.45_/zm of nylon membrane, and the content were measured by HPLC. The result was shown in Table 15.

<164> [Table 15]

<i65> (lδhours later)

<i66> According to the result, transdermal absorption rate of lipoic acid- polyethyleneglycol conjugate is 1.6 folds compared to non-reformed lipoic acid.

<167> Embodiment 17: elasticity improving effect of lipoic acid- polyethyleneglycol conjugate

<168> In this embodiment, a cosmetic containing lipoic acid- polyethyleneglycol conjugate obtained from embodiment 1 was prepared and elasticity improving test of the cosmetics was compared with the cosmetics containing non-reformed lipoic acid to man.

<169> The respective creams of Table 11 were applied to the face of 30 female testee(20~35 years old) 2 times per day for 3 months. Cream containing lipoic acid-polyethyleneglycol conjugate was applied to the right face and cream containing non-reformed lipoic acid was applied to the left face. After the test was completed, their face was compared using cutometer SEM 575(C+K Electronic Co., Germany). The results were revealed in Table 16, and the value ΔR8 of Cutometer SEM 575 indicates viscoelasticity of the skin. As shown in Table 16, the face of the testee who used the cream containing lipoic acid-polyethyleneglycol conjugate showed better skin elasticity improving effect .

<i70> [Table 16]

<i7i> n=30, p<0.05

<172> Embodiment 18: skin whitening effect of lipoic acid~po1yethyleneg1yco1 conjugate

<i73> In this embodiment, a cosmetic containing lipoic acid- po1yethyleneg1yco1 conjugate obtained form embodiment 1 was prepared and the skin whitening test of the cosmetics was compared with the cosmetics containing non-reformed lipoic acid to man.

<i74> The respective creams of Table 11 were applied to the face of 30 female testee(20~35 years old) 2 times per day for 2 months. Cream containing lipoic acid-po1yethyleneg1yco1 conjugate was applied to the right face and cream containing non-reformed lipoic acid was applied to the left face. After the test were completed, their face colors were compared using image analyzer and chromameter(Minolta CR300). The change of lightness(ΔL) was evaluated, and experts' objective evaluation and testees' subjective evaluation were performed. The results are shown in Table 17.

<i75> Followings are skin whitening evaluation standard:

<176> -3: getting worse seriously, -2: getting worse, -1: getting worse a little, 0: not be changed, 1: getting better a little, 2: getting better, 3: getting best.

<177> As shown in Table 17, the face of the testee who used the cream containing lipoic acid-po1yethyleneg1yco1 conjugate showed better skin whitening effect .

<178> [Table 17]

<179> Embodiment 19: improving effect in dandruff, itching and hair growth of lipoic acid-polyethyleneglycol conjugate

<180> In this embodiment, a cosmetic containing lipoic acid- polyethyleneglycol conjugate obtained form embodiment 1 was prepared and the dandruff, itching and baldness improving test of the cosmetic was compared with the cosmetic containing non-reformed lipoic acid to man.

<181> The creams of Table 11 were applied to the head skin of 20 testee(25~50 years old) who has dandruff, itching and baldness symptoms 2 times per day for 2 months.

<182> As shown in Table 18, the head skin of the testee who used the cream containing lipoic acid-polyethyleneglycol conjugate showed improvment in dandruff, itching and hair growth.

<183> [Table 18]

cl84> Followings are other embodiments. In embodiments 20-22, lotion, emusion and cosmetic solution containing the lipoic acid-polyethyleneglycol conjugate obtained from embodiment 1 were prepared. These lotion, emusion and cosmetic solution have anti-oxidant effect, tyrosinase inhibiting effect, skin whitening effect, anti-wrinkle effect, improving dandruff and itching, and promoting effect of hair growth. <i85> Embodiment 20: preparation of a lotoin containing the lipoic acid- polyethyleneglycol conjugate

<i86> Polypyrolidone 0.05g, oleyl alcohol O.lg, polyoxyethylene monooleate 0.2g, perfume 0.2g, paraoxybenzoatemethylester O.lg, small amount of antioxidant and small amount of pigment were added in 8g of 95% ethanol. Said mixed solution, 0.05g of the lipoic acid-polyethyleneglycol conjugate obtained from embodiment 1 and 5g of glycerin were added and mixed to purified water 85.33g. And then, a lotion with skin improving effect and hair growth promoting effect was prepared.

<187> Embodiment 21: preparation of a emulsion containing the lipoic acid- polyethyleneglycol conjugate

<188> 1.2g of cetyl alcohol, 1Og of squalane, 2g of vaseline, 0.2g of paraoxybenzoic acid ethyl ester, Ig of glycerin monostearate, Ig of polyoxyethylene(20mole added) monooleate and O.lg of perfume were mixed and heated.

<i89> 0.5g of the lipoic acid-polyethyleneglycol conjugate obtained from embodiment 1, 5g of dipropylene glycol, 2g of polyethylene glycol-1500, 0.2g of triethanolamine and 76.2g of purified water were dissolved at 75^°C .

<19O> The said two solutions were mixed and emulsified, and then cooled to provide oil in water emulsion with skin improving effect and hair growth promoting effect .

<i9i> Embodiment 22: preparation of a cosmetic solution containing the lipoic acid-polyethyleneglycol conjugate

<192> 2g of ethanol, 1.2g of polyoxyethylenesorbitanemonooleate, 0.3g of carboxymethylcellulose, 0.2g of sodium hyaluronate, 0.2g of vitamin E acetate, 0.2g of glycyrrizinic acid, O.lg of paraoxybenzoic acid ethyl ester, Ig of the lipoic acid-polyethyleneglycol conjugate obtained from embodiment 1 and a proper quantity of pigment were mixed to provide a cosmetic solution with skin improving effect and hair growth promoting effect. [Industrial Applicability]

<193> A lipoic acid-polyethyleneglycol conjugate has anti-oxidant , skin whitening effect, anti-wrinkle effect, preventing acne, relaxing skin stimuli, improving dandruff and itching, and promoting hair growth. So, the derivative of lipoic acid can be used as a component of cosmetics and skin external composition for face skin and head skin.

Claims

[CLAIMS] [Claim 1]

A derivative of lipoic acid of formula I ;

wherein: X is a hetero atom selected from the group consisting of O, N- H and S; n is a fixed number of 4-2,000; R is a functional group selected from the group consisting of -H, alkoxy, benzyloxy, hydroxyl , active ester, active carbonate, acetal, aldehyde, aldehyde hydrate, alkenyl , acrylate, metacrylate, acrylamide, active sulfone, amine, hydrazide, thiol, carboxylate, lipoate, isocyanate, isothiocyanate, maleimide, vinylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, glyoxal , dione, mesylate, tosylate, tresylate, and the functional equivalent thereof.

[Claim 2]

The derivative of lipoic acid of claim 1, wherein said portion of

is molecular weight 200 ~ 100,000, and is selected from a group comprising linear, branched, fork shaped and dumbbell shaped polyethylene glycol.

[Claim 3]

The derivative of lipoic acid of claim 1, wherein said derivative of lipoic acid is liquid or dried form.

[Claim 4]

A skin composition containing a derivative of lipoic acid selected from claim 1-3.

[Claim 5]

The skin composition of claim 4 for anti-oxidant , anti-aging, improving skin wrinkles, whitening, relaxing skin-stimuli, preventing acne, improving dandruff and itching and promoting hair growth.

[Claim 6]

The skin composition of claim 4, the derivative of lipoic acid is present in an amount of 0.001 - 30.0wt% based on the total weight of the composition.

[Claim 7]

The skin composition of claim 4, wherein said composition is in the form of one selected from a group comprising emulsion, gel, hydrophilic liquid, cream, essence, pack, oil~in-water(0/W) , water-in-oil(W/0), powder, ointment, hair tonic, shampoo, rinse, hair lotion and hair cream.