Abstract:
Compositions for topical use having melanin synthesis-inhibiting activity comprising kojic acid or its esters and at least one compound selected from the group consisting of azelaic acid, tropolone, lipoic acid, sorbic acid, glucosamine, derivative of glucosamine, tunicamycin, deoxynojirimycin, glutathione, cystein, hydroquinone, derivative of hydroquinone, dehydroacetic acid, chelidonic acid and lipoamide. The compositions have excellent human skin-whitening effect and anti-suntan effect.

Description:
BACKGROUND OF THE INVENTION 
     The present invention relates to compositions for external use having a melanin synthesis-inhibiting activity, which can be formulated in cosmetic compositions or ointments to exhibit a human skin-whitening effect and anti-suntan effect. 
     It is known that kojic acid and its ester have an effect to inhibit synthesis of melanin (Japanese Tokkyo Kokai Nos. 18739/1978, 7776/1981, 79616/1981, 33207/1984). 
     Kojic acid or its esters have an action to inhibit an activity of tyrosinase which is the enzyme to convert tyrosine to dopa, then to dopa quinone in the pathway of melanin synthesis, whereby the synthesis of melanin is prevented. 
     The present inventor has intensively studied the kojic acid or its esters, in order to obtain more effective melanin synthesis-inhibiting activity, by producing various derivatives of kojic acid or its esters or by using with other drugs. As a result of the study, it has been found a surprising fact that the melanin synthesis can be synergistically inhibited by blending the particular compounds with kojic acid or its esters, and then the present invention has been completed. 
     SUMMARY OF THE INVENTION 
     According to the present invention there can be provided compositions for topical use having the melanin synthesis-inhibiting activity comprising an effective amount of kojic acid or its esters and at least one compound selected from the group consisting of azelaic acid, tropolone, lipoic acid, sorbic acid, glucosamine, derivative of glucosamine, tunicamycin, deoxynojirimycin, glutathione, cystein, hydroquinone, derivative of hydroquinone, dehydroacetic acid, chelidonic acid and lipoamide (hereinafter referred to as &#34;the particular compounds&#34;). Examples of the derivative of glucosamine are, for instance, tetra-O-acetylglucosamine, tetra-O-propanoylglucosamine, O-β-octanoylglucosamine and salts thereof. Examples of the derivative of hydroquinone are, for instance, arbutin. 
    
    
     DETAILED DESCRIPTION 
     As mentioned above it has been known that the kojic acid and its esters have the melanin synthesis-inhibiting activity, and also that the particular compounds can exhibit a whitening effect of human skin. When the two compounds are blended, however, the blended agent can give a surprising effect which is not an additive effect but a synergistic effect which is superior to an effect obtained from each compound, as explained hereinafter. Though the mechanism of this synergistic effect has not yet been clear, it is seemed that a certain delicate correlation occurs in addition to a complementary effect in which a part of effect which cannot be covered with one compound is covered with the other compound. 
     The kojic acid or its esters which is one of the active ingredients of the present invention is preferably represented by the formula: ##STR1## wherein R 1  and R 2  are the same or different, and each is hydrogen atom or an acyl group of 3 to 20 carbon atoms. 
     Non-exclusive examples of the esters are, for instance, kojic acid monoesters such as kojic acid monobutyrate, kojic acid monocaprate, kojic acid monopalmitate, kojic acid monostearate, kojic acid monocinnamoate and kojic acid monobenzoate; kojic acid diesters such as kojic acid dibutyrate, kojic acid dipalmitate, kojic acid distearate and kojic acid dioleate. Preferred monoester is an ester in which a OH group at 5-position of kojic acid is esterified. Esterification can improve stabilities against pH or sun light, while maintaining a melanin synthesis-inhibiting activity equal to that of kojic acid. 
     The composition for topical use of the present invention may be prepared in various forms which can exhibit the melanin synthesis-inhibiting activity and whitening effect and anti-suntan effect, e.g. in a form of cosmetic preparation such as cream, cosmetic lotion, pack or powder, or in a form of quasidrug such as emulsion, lotion, liniment or ointment. In each formulation, there may be used usual additives such as base material, excipient, stabilizer, pigment, fragrance, UV-absorbent, antioxidant, antiseptics, metal deactivator and organic acid. 
     Mixing ratio of kojic acid or its esters to the particular compounds varies with their kind or combination, and is generally 1:0.01 to 1:20 by weight, preferably 1:0.1 to 1:10. Total amount of the active ingredients varies with manner of use, object of use, method of use and preparation form, and is, for example, in cosmetics 0.01 to 20% (% by weight, hereafter the same), preferably 0.5 to 10%, and in ointments 0.01 to 10%, preferably 0.5 to 5%. 
     The active ingredients of the present invention, i.e. kojic acid, its esters and the particular compounds have low toxity to human, and also mixture thereof can be used without any trouble. 
     The present invention is more specifically described and explained by means of the following Examples. It is to be understood that the present invention is not limited to those Examples, and may be made various changes and modifications without departing from the scope or spirit of the present invention. 
     EXAMPLE 1 
     B-16 Cultured cells derived from mouse melanoma cells were inoculated in Eagle&#39;s minimum essential medium containing 10% fetal bovine serum to which kojic acid and the particular compound shown in Table 1 are added in an amount shown in the same Table. The B-16 cells were cultured for 5 days at 37° C. under 5% CO 2  atmosphere, then dispersed with trypsin, and then centrifuged at 1,000 rpm for 5 minutes to collect the cells. Darkness of the cell pellet was observed with naked eyes, and evaluated according to the following standard. 
     -: Same color as that when a melanin synthesis-inhibiting agent is not added. 
     +: Slightly whitened. 
     ++: Considerably whitened. 
     +++: Almost whitened. 
     The results are shown in Table 1. 
     
                       TABLE 1______________________________________The particular compound                 Concentration of                 Kojic acid   Pigmen-Kind      Concentration                 (mM)         tation______________________________________--        --              0.5        ±--        --              1.0        +Azelaic acid     2.5     mM      --         ±     5.0     mM      --         +     2.5     mM      0.5        ++     5.0     mM      0.5        +++Tropolone 0.005   mM      --         ±     0.01    mM      --         +     0.005   mM      0.5        ++     0.01    mM      0.5        +++Lipoic acid     0.25    mM      --         -     0.5     mM      --         +     0.25    mM      0.5        ++     0.5     mM      0.5        +++Sorbic acid     0.5     mM      --         -     1.0     mM      --         +     0.5     mM      0.5        ++     1.0     mM      0.5        +++Glucosamine     1.0     mM      --         -     2.0     mM      --         +     1.0     mM      0.5        ++     2.0     mM      0.5        +++Tetra-0   0.01    mM      --         ±acetyl-   0.02    mM      --         +glucosamine     0.01    mM      0.5        ++     0.02    mM      0.5        +++Tunicamycin     0.05    μg/ml                     --         ±     0.1     μg/ml                     --         +     0.05    μg/ml                     0.5        ++     0.1     μg/ml                     0.5        +++Glutathione     5.0     mM      --         -     10.0    mM      --         -     5.0     mM      0.5        +     10.0    mM      0.5        ++Cysteine  2.0     mM      --         -     4.0     mM      --         -     2.0     mM      0.5        +     4.0     mM      0.5        ++Hydroquinone     0.01    mM      --         -     0.05    mM      --         +     0.01    mM      0.5        ++     0.05    mM      0.5        +++Arbutin   0.01    mM      --         -     0.05    mM      --         +     0.01    mM      0.5        ++     0.05    mM      0.5        +++Dehydroacetic     0.3     mM      --         ±acid      0.6     mM      --         +     0.3     mM      0.5        ++     0.6     mM      0.5        ++ +Chelidonic     1.0     mM      --         -acid      2.0     mM      --         +     1.0     mM      0.5        ++     2.0     mM      0.5        +++Lipoamide 0.1     mM      --         -     0.2     mM      --         +     0.1     mM      0.5        ++     0.2     mM      0.5        +++______________________________________ 
    
     EXAMPLE 2 
     On the inner side of right upper arm of each volunteer (thirty healthy men and women), a test site (2 cm×2 cm) was provided. Before irradiation with ultraviolet rays the test site was carefully washed with warm water and was wrapped around the test site with aluminum foil so that only the test site was irradiated with ultraviolet rays. The irradiation was carried out three consecutive days at a dose of 0.8×10 7  erg/cm 3  per each irradiation per one day with four lamps (FL20S.BLB Lamp×2 and FL20S.E-30 Lamp×2 available from Toshiba Co., Ltd.) which were set at a distance of 10 cm from the test site. After the irradiation, the following test composition (vanishing cream) was applied everyday to the irradiated site three times per day (morning, noon, night). After three weeks, degree of pigmentation of the test site was observed with naked eyes. The improvement of the pigmentation was evaluated by the number of volunteers in three degrees, i.e. very effective, effective or non-effective. The results are shown in Table 2. 
     (Test Composition) 
     
         ______________________________________(Test composition)     Part by weight______________________________________(A)  Kojic acid ester shown in Table 2                      1.00Polyoxyethylene (40) monostearate                      2.00Glycerol monostearate 5.00(selfemulsifying type)Stearic acid          5.00Behenyl alcohol       1.00Liquid paraffin       1.00Glyceryl trioctanoate 10.00Antiseptics           properFragrance             slight(B)  The particular compound                      1.00shown in Table 21,3-Butylene glycol   5.00Purified water        remain______________________________________ 
    
     The ingredients (A) are melted by heating to obtain an oil phase. Separately the ingredients (B) are dissolved by heating to prepare an aqueous phase. The aqueous phase is added to the oil phase, and the resulting mixture is emulsified with stirring, then cooled to give a vanishing cream. 
     
                                           TABLE 2__________________________________________________________________________                    Number of the volunteers                    Very      Non-Kojic acid ester       The particular compound                    effective                         Effective                              effective__________________________________________________________________________--          Azelaic acid 0     5   25--          Tropolone    1     5   24--          Lipoic acid  0     6   24--          Sorbic acid  0     6   24--          Glucosamine  1     7   22--          Tetra-O-acetylglucosamine                    2     9   19--          Tunicamycin  2     6   22--          Glutathione  0     4   26--          Cystein      0     4   26--          Hydroquinone 2     8   20--          Arbutin      2     8   20--          Dehydroacetic acid                    0     6   24--          Chelidonic acid                    0     6   24--          Lipoamide    0     5   25Kojic acid monostearate         --         3     6   21--          Azelaic acid 5    15   10--          Tropolone    6    13   11--          Lipoic acid  4    15   11--          Sorbic acid  4    15   11--          Glucosamine  6    13   11--          Tetra-O-acetylglucoamine                    8    20    2--          Tunicamycin  8    15    7--          Glutathione  4    12   14--          Cytein       4    10   16--          Hydroquinone 6    22    2--          Arbutin      5    20    5--          Dehydroacetic acid                    5    13   12--          Chelidonic acid                    4    15   11--          Lipoamide    4    13   13Kojic acid dipalmitate         --         2     8   20--          Azelaic acid 4    16   10--          Tropolone    5    15   10--          Lipoic acid  4    14   12--          Sorbic acid  4    14   12--          Glucosamine  5    17    8--          Tetra-O-acetylglucosamine                    8    19    3--          Tunicamycin  8    13    9--          Glutathione  5    14   11--          Cystein      4    14   12--          Hydroquinone 7    21    2--          Arbutin      7    19    4--          Dehydroacetic acid                    4    15   11--          Chelidonic acid                    4    16   10--          Lipoamide    4    15   11__________________________________________________________________________ 
    
     The followings are typical formulations of the melanin synthesis-inhibiting agent of the present invention. It is to be understood that the present invention is not limited to the formulations. 
     
         ______________________________________Lotion               Part by weight______________________________________Polyoxyethylene (60) hydrogenated                1.00castor oilEthanol              15.00Citric acid          0.10Sodium citrate       0.301,3-Butylene glycol  4.00Kojic acid           1.00Tetra-O-acetyl-      0.50glucosamineAntiseptics          properFragrance            slightPurified water       remain______________________________________ 
    
     The all ingredients are homogeneously mixed and dissolved with stirring to give a lotion. 
     
         ______________________________________Emulsion              Part by weight______________________________________(A)    Polyoxyethylene (20) behenyl                     0.50  ether  Polyoxyethylene (60) sorbitol                     1.00  tetraoleate  Glyceryl monostearate                     1.00  (hydrophilic type)  Stearic acid       0.50  Behenyl alcool     0.50  Avocado oil        1.00  Natural vitamin E  0.02  Kojic acid monopalmitate                     2.00  Antiseptics        proper  Fragrance          slight(B)    1,3-Butylene glycol                     5.00  Carboxyvinyl polymer                     0.10  Sodium N-lauroyl-L-glutamate                     0.50  Glutathione        1.00  Tunicamycin        0.10  Purified water     remain______________________________________ 
    
     The ingredients (A) are melted by heating to obtain an oil phase. Separately the ingredients (B) are dissolved by heating to prepare an aqueous phase. The aqueous phase is added to the oil phase, and the resulting mixture is emulsified with stirring, then cooled to give an emulsion. 
     
         ______________________________________Jellied pack     Part of weight______________________________________Citric acid      0.20Propylene glycol 4.00Glycerin         4.00Ethanol          2.00Carboxyvinyl polymer            1.00Pottasium carbonate            0.60Kojic acid       0.50Azelaic acid     1.50Antiseptics      properFragrance        slightPurified water   remain______________________________________ 
    
     To all components are homogeneously mixed and dissolved with stirring to give a jellied pack. 
     
         ______________________________________Creamy pack            Part by weight______________________________________(A)  Polyoxyethylene (20) behenyl                      1.00etherPolyoxyethylene (40) sorbitol                      2.00tetraoleateGlycerin monostearate 2.00(hydrophilic type)Behenyl alcohol       3.00Squalane              25.00Glycerine octanoate   10.00Natural vitamin E     0.04Kojic acid monocinnamoate                      2.00Antiseptics           properFragrance             slight(B)  1,3-Butylene glycol   5.00Sodium dl-pyrrolidonecarboxylate                      1.50Citric acid           0.04Arbutin               0.50Purified water        remain______________________________________ 
    
     The ingredients (A) are melted by heating to obtain an oil phase. Separately, the ingredients (B) are dissolved by heating to prepare an aqueous phase. The aqueous phase is added to the oil phase, and the resulting mixture is emulsified with stirring, then cooled to give a creamy pack. 
     
         ______________________________________Ointment              Part by weight______________________________________(A)    Polyoxyethylene (60) sorbitan                     1.00  monostearate  Polyoxyethylene (60) sorbitol                     1.50  tetraoleate  Glycerin monostearate                     1.50  (selfemulsifying type)  Beeswax            2.00  Paraffin           2.00  Stearic acid       3.00  Behenyl alcohol    3.00  Shea butter        12.00  Liquid paraffin    5.00  Natural vitamin E  0.04  Methyl polysiloxane                     0.01  Kojic acid monobenzoate                     3.00  Antiseptics        proper  Fragrance          slight(B)    1,3-Butylene glycol                     5.00  Citric acid        0.30  Sodium dl-lauroyl-L-glutamate                     0.50  Lipoic acid        2.00  Purified water     remain______________________________________ 
    
     The ingredients (A) are melted by heating to obtain an oil phase. Separately, the ingredients (B) are dissolved by heating to prepare an aqueous phase. The aqueous phase is added to the oil phase, and the resulting mixture is emulsified with stirring, then cooled to give an ointment. 
     
         ______________________________________Whitening powder  Part by weight______________________________________Octyldodecyl myristate             1.0Kojic acid        2.0Lipoamide         1.0Cystein           2.0Fragrance         slightMaltitol          remain______________________________________ 
    
     The all ingredients are homogeneously mixed to give a whitening powder.