Patent Publication Number: US-2010113590-A1

Title: Adam inhibitor

Description:
FIELD OF THE INVENTION 
     The present invention relates to a novel ADAM inhibitor. 
     BACKGROUND ART 
     A group of the membrane type metalloproteases called ADAM (a disintegrin and metalloprotease) are enzymes which play important roles in interactions between cells and extracellular matrices and known to be greatly involved in the differentiation and proliferation of cells, extension and myelination of axons and the like (see, for example, Non-Patent Reference 1). In addition, ADAM as well as the matrix metalloprotease (MMP) has a function of cutting various growth factors including heparin-binding EGF-like growth factor (HB-EGF) and tumor necrosis factor (TNF), transforming growth factor; TGF, cytokines, amyloid precursor protein (APP) and many other membrane proteins on the cell surface and releasing them out of the cell. It is known that ADAM is highly expressed in the pathologic tissues of various malignant tumors (glioma, lung cancer, breast cancer, etc.), rheumatism, and in the cerebrum of patients with Alzheimer&#39;s disease, and promotes proliferation and infiltration of the cell or induces the angiogenesis essential for infiltration of cancer cells (see, for example, Non-Patent References 2-6). Therefore, suppression of ADAM activity is considered to be very important in preventing progression of the disease such as cancer, rheumatism, Alzheimer&#39;s disease and the like. 
     Non-Patent Reference 1: Yang P, Baker K A, Hagg T. The ADAMs family: Coordinators of nervous system development, plasticity and repair. Prog Neurobiol 2006; 79: 73-94. 
     Non-Patent Reference 2: Arribas J, Bech-Serra J J, Santiago-Josefat B. ADAMs, cell migration and cancer. Cancer Metastasis Rev 2006; 25: 57-68. 
     Non-Patent Reference 3: Kodama T, Ikeda E, Okada A et al. ADAM12 is selectively overexpressed in human glioblastomas and is associated with glioblastoma cell proliferation and shedding of heparin-binding epidermal growth factor. Am J Pathol 2004; 165: 1743-53. 
     Non-Patent Reference 4: Liu P C, Liu X, Li Y et al. Identification of ADAM10 as a Major Source of HER2 Ectodomain Sheddase Activity in HER2 Overexpressing Breast Cancer Cells. Cancer Biol Ther 2006; 5: 657-64. 
     Non-Patent Reference 5: Rocks N, Paulissen G, Quesada Calvo F et al. Expression of a disintegrin and metalloprotease (ADAM and ADAMTS) enzymes in human non-small-cell lung carcinomas (NSCLC). Br J Cancer 2006; 94: 724-30. 
     Non-Patent Reference 6: Asakura, M. et al. 2002, Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy, Nat. Med. 8: 35-40. 
     DISCLOSURE OF THE INVENTION 
     Problems to be Solved by the Invention 
     While TAPI-1{N—(R)-(2-(Hydroxyaminocarbonylmethyl)-4-Methylpentanoyl-L-NaI-L-Alanine2-Aminoethyl amide(L-NaI:L-3-(2′-Naphthyl)alanine)} and TAPI-2{N—(R)-(2-(Hydroxyaminocarbonyl)methyl)-4-Methylpentanoyl-L-t-Butyl-Glycyl-L-Alanine2-Aminoethyl amide} are known as ADAM inhibitors, ADAM inhibitory ability of those substances is not sufficient and their safety as external medications has not been established. Therefore, there has been a need for developing a safer and more efficacious agent. 
     The present invention has been attained in view of the above situation and for the purpose of providing an ADAM inhibitor, which has an ADAM inhibiting action and can prevent or ameliorate the diseases caused by increase of ADAM activity. 
     Means for Solving the Problems 
     ADAM is an enzyme which exists on the cell surface, and it releases the growth factors including HB-EGF, TNF-α, TGF-α, and cytokines, amyloid precursors, etc. out of the cell membrane, and activates them. One of the important mechanisms for induction or aggravation of diseases including cancers, rheumatism or Alzheimer&#39;s disease is considered that ADAM is activated or its expression is enhanced by the signal of malignant transformation or external stimuli leading to promotion of release/activation of the growth factors such as HB-EGF and cytokines as well as differentiation, proliferation and migration of the cell. Therefore, it is assumed that induction or progression of the conditions such as cancers, rheumatism or Alzheimer&#39;s disease could be prevented or ameliorated by suppressing ADAM activity leading to suppressing differentiation, proliferation or filtration of the cell. Further, the invention could not only be applied to the diseases caused by increase of ADAM activity but also could prevent or ameliorate the wrinkle by application to the wrinkle caused by hyperplasia of the epidermal cell. 
     In searching for a new compound which may inhibit ADAM, the inventors found that certain ascorbic acid derivatives and salts thereof have high ADAM inhibitory activity, thus leading to attainment of the invention. 
     The invention is an ADAM inhibitor characterized by comprising an ascorbic acid derivative represented by the general formula (I) described below or a salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein, R represents a linear or branched alkyl group having 1 to 22 carbon atoms. 
     The ascorbic acid derivatives of the invention are those which prevent abnormal differentiation, proliferation and migration of the cell by inhibiting or suppressing ADAM activity. 
     Further, the invention provides a method for inhibiting ADAM characterized in that the ADAM inhibitor is applied to the skin to prevent or ameliorate the conditions caused by increase of ADAM activity. 
     EFFECT OF THE INVENTION 
     The ADAM inhibitor of the invention can inhibit ADAM activity present in the tissue to suppress very effectively the release/activation of different growth factors and cytokines on the cell surface as well as differentiation, proliferation and migration of the cell. 
     According to the method of the invention for inhibiting ADAM, the conditions caused by increase of ADAM activity can be prevented or ameliorated effectively using an ADAM inhibitor described above. 
    
    
     BEST MODE FOR CARRYING OUT THE INVENTION 
     The most preferred embodiments of the invention will be described below. An ascorbic acid derivative or a salt thereof used in the invention is represented as general formula (I) described below. 
     
       
         
         
             
             
         
       
     
     wherein, R represents a linear or branched alkyl group having 1 to 22 carbon atoms. 
     R in the ascorbic acid derivative (1) of the inventive compounds is a linear or branched alkyl group having 1 to 22 carbon atoms, preferably a linear or branched alkyl group having 4 to 18 carbon atoms, more preferably a linear or branched alkyl group having 12 to 18 carbon atoms. Such groups include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosane, heneicosane, docosane, etc., preferably, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, etc., more preferably, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, etc. 
     Ascorbic acid derivatives of the invention include, for example, 2-O-methylascorbic acid, 2-O-ethylascorbic acid, 2-O-propylascorbic acid, 2-O-isopropylascorbic acid, 2-O-butylascorbic acid, 2-O-isobutylascorbic acid, 2-O-tert-butylascorbic acid, 2-O-pentylascorbic acid, 2-O-hexylascorbic acid, 2-O-heptylascorbic acid, 2-O-octylascorbic acid, 2-O-(2-ethylhexyl)ascorbic acid, 2-O-nonylascorbic acid, 2-O-decylascorbic acid, 2-O-undecylascorbic acid, 2-O-dodecylascorbic acid, 2-O-tridecylascorbic acid, 2-O-tetradecylascorbic acid, 2-O-pentadecylascorbic acid, 2-O-hexadecylascorbic acid, 2-O-heptadecylascorbic acid, 2-O-octadecylascorbic acid, 2-O-nonadecylascorbic acid, 2-O-eicosane ascorbic acid, 2-O-heneicosane ascorbic acid, 2-O-docosane ascorbic acid, etc. Among them, 2-O-dodecylascorbic acid and 2-O-octadecylascorbic acid are particularly preferable. 
     Ascorbic acid derivatives used in the invention include, besides free acids, medically acceptable salt forms thereof. These salts include, for example, but not limited to, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, amine salts such as methylamine salts, dimethylamine salts, trimethylamine salts, methylpiperidine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts and lysine salts, ammonium salts or basic amino acid salts. 
     Ascorbic acid derivatives and salts thereof may be produced according to the known producing methods. 
     The ADAM inhibitor comprising an ascorbic acid derivative or a salt thereof may be used as but not limited to dermatological external agents, powders, granules, ampules and injections. 
     In case of using an ADAM inhibitor of the invention in a dermatological external agent, the combination amount of an ascorbic acid derivative or a salt thereof varies depending on the its use aspect and product form, being, for example, but not particularly limited to preferably 0.001-10% by mass, more preferably 0.005-5% by mass, even more preferably 0.01-1% by mass based on the total amount. 
     In the specification here, the “dermatological external agents” include cosmetics, drugs and quasi drugs, etc. Its formulations include any such as an aqueous, solubilizing, emulsified, oil, gel, paste, ointment, aerosol, water-oil bilayer and water-oil-powder three layer systems. They also include those carried on the sheeted base. 
     The dermatological external agents can also adopt any product forms and uses. For example, it can be used as an external agent for the face, body or scalp including lotions, emulsions, creams and packs. 
     The dermatological external agent may mix properly as needed besides the above described ascorbic acid derivative or a salt thereof, any other components used in the dermatological external agent including ordinary cosmetics and drugs, and produced according to the conventional methods depending on the intended formulation. For example, an ascorbic acid derivative or a salt thereof may be mixed with one or two or more of the ingredients below to prepare a dermatological external agent. 
     Ultraviolet light absorbing agents include, for example, ultraviolet absorber of benzoic acid system such as para-aminobenzoic acid (hereinafter, abbreviated as PABA), PABA monoglycerin ester, N,N-dipropoxy PABA ethyl ester, N,N-diethoxy PABA ethyl ester, N,N-dimethyl PABA ethyl ester, N,N-dimethyl PABA butyl ester, and N,N-dimethyl PABA methyl ester, etc.; ultraviolet absorber of anthranilic acid system such as homomethyl-N-acetylanthranilate; ultraviolet absorber of salicylic acid system such as amyl salicylate, menthyl salicylate, homomethyl salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, p-isopropanol phenyl salicylate, etc.; ultraviolet absorber of cinnamic acid system such as octyl cinnamate, ethyl-4-isopropyl cinnamate, methyl-2,5-diisopropyl cinnamate, ethyl-2,4-diisopropyl cinnamate, methyl-2,4-diisopropyl cinnamate, propyl-p-methoxy cinnamate, isopropyl-p-methoxy cinnamate, isoamyl-p-methoxy cinnamate, octyl-p-methoxy cinnamate (2-ethylhexyl-p-methoxy cinnamate), 2-ethoxyethyl-p-methoxy cinnamate, cyclohexyl-p-methoxy cinnamate, ethyl-α-cyano-β-phenyl cinnamate, 2-ethylhexyl-α-cyano-β-phenyl cinnamate, glycerylmono-2-ethylhexanoyl-dipara-methoxy cinnamate, and methyl bis(trimethylsiloxane)silylisopentyl trimethoxy cinnamate, etc.; 3-(4′-methylbenzylidene)-d,1-camphor; 3-benzylidene-d,1-camphor; urocanic acid; urocanic acid ethyl ester, 2-phenyl-5-methylbenzoxazole, 2,2′-hydroxy-5-methylphenylbenzotriazole; 2-(2′-hydroxy-5′-t-octylphenyl)benzotriazole; 2-(2′-hydroxy-5′-methylphenylbenzotriazole; dibenzaladine, dianisoylmethane, 4-methoxy-4′-t-butyldibenzoylmethane; 5-(3,3-dimethyl-2-norbornylidene)-3-pentane-2-one; dimorpholinopyridazinone, etc. and any one or two or more may be used. 
     Ultraviolet light scattering agents include, for example, powders such as titanium oxide, particulate titanium oxide, zinc oxide, particulate zinc oxide, ferric oxide, particulate ferric oxide, and ceric oxide, etc. 
     For these ultraviolet light scattering agent, a spicular, spindle, spherical or granular powder is usually used. In addition, particulate powders which have the particle size of not more than 0.1 μm is preferable. 
     Also preferable are ultraviolet light scattering agents silicone-treated by methyl hydrogen polysiloxane or silane coupling agent; metallic soap-treated; fluorine-treated by perfluoroalkyl phosphate diethanolamine salt or perfluoroalkyl silane; hydrophobilized-treated by dextrin fatty acid ester treatment and the like. 
     Liquid oils include, for example, avocado oil, camellia oil, turtle oil, macadamia nuts oil, corn oil, mink oil, olive oil, rape seed oil, yolk oil, sesame oil, persic oil, wheat embryo oil, sasanqua oil, castor oil, flaxseed oil, safflower oil, cottonseed oil, perilla oil, soybean oil, peanut oil, tea seed oil, kaya oil, rice bran oil, shinagiri oil, Japan tung oil, jojoba oil, embryo oil, triglycerin, and the like. 
     Solid oils include, for example, cocoa butter, coconut oil, equine tallow, hydrogenated coconut oil, palm oil, beef tallow, mutton tallow, hydrogenated beef oil, palm kernel oil, lard, bovine bone tallow, Japan kernel oil, hydrogenated oil, bovine leg tallow, Japan wax, hydrogenated castor oil, and the like. 
     Waxes include, for example, beeswax, candelilla wax, cotton wax, carnauba wax, baybery wax, ibota wax, spermaceti wax, montan wax, rice wax, lanolin, kapok wax, lanolin acetate, liquid lanolin, sugarcane wax, lanolin fatty acid isopropyl, hexyl laurate, reduced lanolin, jojoba wax, hard lanolin, shellac wax, POE lanolin alcohol ether, POE lanolin alcohol acetate, POE cholesterol ether, lanolin fatty acid polyethylene glycol, POE hydrogenated lanolin alcohol ether, and the like. 
     Hydrocarbon oils include, for example, liquid paraffin, ozokerite, squalane, pristane, paraffin, ceresin, squalene, vaseline, microcrystalline wax, polyethylene wax, Fischer-Tropsch wax, etc. 
     Higher fatty acids include, for example, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, undecylenic acid, tolic acid, linoleic acid, linolenic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), etc. 
     Higher alcohols include, for example, straight chain alcohols (e.g., lauryl alcohol, cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, oleyl alcohol, cetostearyl alcohol, etc.); branched chain alcohols (e.g., monostearyl glycerin ether (batyl alcohol), 2-decyltetradecynol, lanolin alcohol, cholesterol, phytosterol, hexyldodecanol, octyldodecanol, etc.) and the like. 
     Synthesized ester oils include isopropyl myristate, cetyl octanoate, octyldodecyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, decyl oleate, hexyldecyl dimethyloctanoate, cetyl lactate, myristyl lactate, lanolin acetate, isocetyl stearate, isocetyl isostearate, cholesteryl 12-hydroxystearate, ethylene glycol di-2-ethyl hexanoate, dipentaerythritol fatty acid ester, N-alkyl glycol monoisostearate, neopentyl glycol dicaprate, diisostearyl malate, glycerin di-2-heptylundecanoate, trimethylolpropane tri-2-ethyl-hexanoate, trimethylolpropane triisostearate, pentaerythritol tetra-2-ethylhexanoate, glycerin tri-2-ethyl hexanoate, glycerin trioctanoate, glycerin triisopalmitate, trimethylolpropane triisostearate, cetyl 2-ethyl hexanoate, 2-ethylhexyl palmitate, glycerin trimyristate, glyceride tri-2-heptylundecanoate, castor oil fatty acid methyl ester, oleyl oleate, acetoglyceride, 2-heptylundecyl palmitate, diisobutyl adipate, N-lauroyl-L-glutamic acid-2-octyldodecyl ester, di-2-heptylundecyl adipate, ethyl laurate, di-2-ethylhexyl sebacate, 2-hexyldecyl myristate, 2-hexyldecyl palmitate, 2-hexyldecyl adipate, 2-ethylhexyl succinate, triethyl citrate, polyoxyethylene-polyoxypropylene random polymer methyl ether, etc. 
     Silicone oils include, for example, chain polysiloxanes (e.g., dimethyl polysiloxane, methylphenylpolysiloxane, diphenylpolysiloxane, etc.); cyclic polysiloxanes (e.g., octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, dodecamethylcyclohexasiloxane, etc.), silicone resins which form three dimensional network structures, silicone gums, a wide variety of denatured polysiloxanes (amino-denatured polysiloxane, polyether-denatured polysiloxane, alkyl-denatured polysiloxane, fluorine-denatured polysiloxane, etc.) and the like. 
     Others include, for example, humectants such as polyethylene glycol, glycerin, 1,3-butyleneglycol, erythritol, sorbitol, xylitol, maltitol; thickeners such as cellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylhydroxypropylcellulose, methylcellulose, carboxymethylcellulose, quinceseed, carrageenan, pectin, mannan, curdlan, chondroitin sulfate, starch, galactan, dermatan sulfate, glycogen, acacia gum, heparan sulfate, hyaluronic acid, sodium hyaluronate, tragacanth gum, keratan sulfate, chondroitin, xanthan gum, mucoitin sulfate, hydroxyethyl guar gum, carboxymethyl guar gum, guar gum, dextran, kerato sulfate, locust bean gum, succinoglucan, caronic acid, chitin, chitosan, carboxymethylchitin and agar, etc.; lower alcohols such as ethanol; antioxidants such as butylhydroxytoluene, tocopherol, and phytin; antibacterial agents such as benzoic acid, salicylic acid, sorbic acid, paraoxybenzoic acid alkyl ester, and hexachlorophene; organic acids such as acyl sarcosine (e.g., sodium lauloyl sarcosine), glutathione, citric acid, malic acid, tartaric acid and lactic acid; vitamin A and its derivatives, vitamin Bs such as vitamin B6 hydrochloride, vitamin B6 tripalmitate, vitamin B6 dioctanoate, vitamin B2 and its derivatives, vitamin B12, and vitamin B15 and its derivatives, vitamin Cs such as ascorbic acid, ascorbic acid sulfate ester (salt), ascorbic acid phosphate ester (salt), and ascorbic acid dipalmitate, vitamin Es such as α-tocopherol, β-tocopherol, δ-tocopherol, and vitamin E acetate; vitamins such as vitamin Ds, vitamin H, pantothenic acid, and pantethine; saponins such as nicotinamide, benzyl nicotinate, γ-orizanol, allantoin, glycyrrhizic acid (salt), glycyrrhetic acid and its derivatives, hinokitiol, bisabolol, eucalyptone, thymol, inositol, saikosaponin, ginseng saponin,  Luffa cylindrica  saponin, and soapberry saponin; various drugs such as pantothenylethyl ether, ethynylestradiol, tranexamic acid, arbutin, cepharanthin, and placenta extract, plant extracts such as  Rumex japonicus , Clara,  Nuphar japonicum  DC, orange, sage,  Achillea alpina, Malva sylvestris, Swertia japonica , thyme, Japanese angelica, bitter orange peel, birch, Field Horsetail,  Luffa cylindrica , common horsechestnut, Saxifragaceae, arnica, lily, sagebrush, paeoniae radix, aloe,  Gardenia jasminoides , Sawara cypress, Hawthorn extract,  Hypericum perforatum  extract, iris-inextract, Gambir extract, ginkgo leaf extract, ibukijyakou extract,  Foeniculum vulgare  extract, Oolong tea extract, water-lily extract, Rosae Multiflorae Fructus extract,  Plectranthus japonicus  extract, Scutellariae Radix extract, Phellodendri Cortex extract,  Lamium album  extract,  G. uralensis  extract,  Gardenia jasminoides  extract, black tea extract,  Tamarix chinensis  Lour extract,  Potentilla Erecta  extract, rose extract,  Luffa cylindrica  extract, peppermint extract, rosemary extract, and royal jelly extract, pigment; non-ionic surfactants such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyethylene glycol monooleate, polyoxyethylene alkyl ether, polyglycol diether, lauroyldiethanol amide, fatty acid isopropanolamide, maltitolhydroxy fatty acid ether, alkylated polysaccharide, alkyl glucoside, and sugar ester, cationic surfactants such as stearyltrimethylammonium chloride, benzalkonium chloride, and laurylamine oxide, anionic surfactants such as sodium palmitate, sodium laurate, sodium lauryl acid, potassium lauryl sulfate, alkylsulfuric acid triethanolamine ether, turkey-red oil, linear dodecylbenzene sulfate, polyoxyethylene hydrogenated castor oil maleic acid, and acylmethyl taurine; ampholytic surfactants; neutralizers; antioxidants such as δ-tocopherol and butylhydroxytoluene, and preservatives such as phenoxyethanol and paraben. 
     The above described ingredients are only illustrative and the invention is not limited to them. Additionally, these ingredients may be mixed being combined appropriately according to description depending on the desired form. 
     The ADAM inhibitor of the invention may be used as a drug intended to prevent or ameliorate the conditions caused by increase of ADAM activity. 
     In order to formulate the ADAM inhibitor of the invention in such uses, for example, powders, granules, ampoules, injections, isotonic solutions and the like are prepared according to ordinary methods. In the case of preparing oral solid preparations, added are excipients and if needed binders, wetting agents, disintegrators, surfactants, lubricants, dispersing agents, flavors and correctives followed by preparation as tablets, coated tablets, granules, capsules or the like according to conventional methods. 
     The excipients used include, for example, lactose, glucose, sorbitol, cornstarch and mannitol, etc.; the binders include, for example, polyvinyl alcohol, polyvinyl ether, ethylcellulose, acacia gum, gelatin, hydroxypropylcellulose and polyvinylpyrrolidone, etc; the disintegrators include calcium carbonate, calcium citrate, dextrin, starch, gelatin powder, etc.; the lubricants include calcium carbonate, calcium citrate, talc, polyethyleneglycol, etc.; the coloring agents include cocoa powder, mint flavoring acid and mint oil, etc. These tablets and granules may be coated properly if needed by sugar, gelatin and others. 
     In the case of preparing the injections, added are if needed pH adjusting agents, buffers, surfactants, solubilizers, solvents, stabilizers, preservatives and the like and prepared as subcutaneous, intramuscular or intravenous injections. 
     In the method of the invention for inhibiting ADAM, the ascorbic acid derivatives or salts thereof may be applied in any forms singly or in combination with any other ingredients as long as they can be applied to the skin and can attain the purpose of the invention. In addition, the location of the skin where they are applied to is not limited but includes the skin of all over the body surface including the scalp. In addition, they may be applied by oral administration or by injection. 
     Further, use of the ADAM inhibitor comprising an ascorbic acid derivative or a salt thereof is not limited to treatment or prevention of different diseases adversely affected by growth or differentiation of the skin cell due to the activation of ADAM as described above, but includes any uses which can exert the effect by inhibiting the ADAM activity. The invention for example, may not only be applied to the diseases caused by increase of the ADAM activity, but also applied to the wrinkle caused by hyperplasia of the epidermal cells thereby the wrinkle may be prevented or ameliorated. 
     EXAMPLES 
     Examples will now be given to describe the present invention in more detail. The invention is not intended to be limited to them. The combination amounts herein are % by mass. 
     1. Exploring a New ADAM Inhibitor 
     For the ADAM inhibiting effect, the TNF-α which is cut out to be released from the membrane of the U937 cell derived from the human lymphoma through the action of ADAM was used as an index, and the inhibiting effect on the TNF-α release by the agents was assessed. A new ADAM inhibitor was explored by screening different compounds according to the present method. 
     The U937 cells derived from the human lymphoma were seeded to the 48-well plate adjusting the number of the cells to 1×10 5  cells/0.25 ml and cultured at 37° C. overnight. The medium which contained 5 μg/ml or 30 μg/ml of an ascorbic acid derivative was added and incubated at 37° C. for 30 min. to be pretreated. 10 nM PMA (phorbol ester: 12-O-tetradecanoylphorbol-acetate; Sigma P8139) was then added and cultured at 37° C. for 6 hours. After completion of the treatment, the supernatant of the culture was collected, centrifuged and the cell-free supernatant was cryopreserved at −20° C. The assay of the released hTNF-α was performed using the hTNF-α Duo-Set ELISA kit from R &amp; D Ltd. Each supernatant of the culture was diluted 5-folds with the medium, then 100 ml each was added to the 96-well plate and measured according to the protocol of R &amp; D Ltd. The absorbance at 450-570 nm of each well was measured by the measurement kit and concentrations of the samples were obtained from the standard curve. The inhibition rates were calculated according to the following equation wherein A0 is the absorbance of 0% inhibiting control (the medium containing only PMA), A100 is the absorbance of 100% inhibiting control (only the medium) and AS is the absorbance of the sample. 
       The inhibition rate (%)=( A 0− AS )/( A 0− A 100)×100 
     Consequently, a high suppressing effect on HB-EGF release was noted for 2-O-dodecyl ascorbic acid and 2-O-octadecyl ascorbic acid which have particularly greater number of carbon atoms among the inventive ascorbic acid derivatives suggesting that they inhibit the ADAM activity. The release suppressing rate of each ascorbic acid derivative is shown in Table 1. 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 1 
               
             
            
               
                   
                   
               
               
                   
                 Inhibition rate (%) 
                   
               
               
                   
                 Concentration 
               
            
           
           
               
               
               
               
            
               
                   
                 Substance tested 
                 5 μg/mL 
                 30 μg/mL 
               
               
                   
                   
               
               
                   
                 2-O-dodecyl ascorbic acid 
                 18.25 
                 60.07 
               
               
                   
                 2-O-octadecyl ascorbic acid 
                 15.19 
                 82.70 
               
               
                   
                   
               
            
           
         
       
     
     Examples of preparations containing ascorbic acid derivatives or salts thereof according to the invention will be shown below, but the invention is not to be limited to them. 
     Preparation Example 1 
     Injection 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
                 2-O-dodecyl ascorbic acid 
                 100 mg 
               
               
                   
                 Chloroform 
                  5 ml 
               
               
                   
                 Tween-80 
                 100 mg 
               
               
                   
                 Sterile distilled water 
                  10 ml 
               
               
                   
                   
               
            
           
         
       
     
     (Procedure) 
     100 mg of finely powdered 2-O-dodecyl ascorbic acid was dissolved in 5 ml of chloroform. 10 mg of Tween-80 was added and mixed, then filtrated through a millipore filter followed by evaporation to dryness with a sterile evaporator. 10 ml of sterile distilled water was added and mixed vigorously, then sonicated and filled into an ampoule to prepare an injection. 
     Preparation Example 2 
     Emulsion 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Stearic acid 
                 2.5 
               
               
                   
                 Cetyl alcohol 
                 1.5 
               
               
                   
                 Vaseline 
                 5.0 
               
               
                   
                 Liquid paraffin 
                 5.0 
               
               
                   
                 Polyoxyethylene (10 mol) monooleate ester 
                 2.0 
               
               
                   
                 Polyethylene glycol 1500 
                 3.0 
               
               
                   
                 Triethanolamine 
                 1.0 
               
               
                   
                 Carboxy vinyl polymer 
                 0.05 
               
               
                   
                 2-O-dodecylascorbic acid 
                 2.0 
               
               
                   
                 Sodium bisulfite 
                 0.01 
               
               
                   
                 Ethylparaben 
                 0.2 
               
               
                   
                 Flavor 
                 q.s. 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                   
               
            
           
         
       
     
     (Procedure) 
     Carboxy vinyl polymer is dissolved in a little amount of the purified water (phase A). Polyethylene glycol 1500, triethanolamine and 2-O-dodecylascorbic acid are added to the remaining purified water, dissolved with heating, then maintained at 70° C. (aqueous phase). Other ingredients are mixed, melted with heating, then maintained at 70° C. (oil phase). The oil phase is added to the aqueous phase to pre-emulsify, then phase A is added to emulsify homogeneously with a homomixer. After emulsification, it is cooled to 30° C. while mixing well to obtain an emulsion. 
     Preparation Example 3 
     Lotion 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Ethanol 
                 5.0 
               
               
                   
                 Carboxy vinyl polymer 
                 0.3 
               
               
                   
                 Polyoxyethylene (15 mol) oleyl ether 
                 0.8 
               
               
                   
                 1,3-Butylene glycol 
                 5.0 
               
               
                   
                 2-O-octadecylascorbic acid 
                 2.0 
               
               
                   
                 Citric acid 
                 0.03 
               
               
                   
                 Sodium citrate 
                 0.07 
               
               
                   
                 Methylparaben 
                 0.1 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                   
               
            
           
         
       
     
     (Procedure) 
     Citric acid, sodium citrate and 2-O-octadecylascorbic acid were dissolved in the purified water to make an aqueous phase. On the other hand, other ingredients were dissolved with stirring. This was added to the aqueous phase, and made homogeneous to obtain a lotion. 
     Preparation Example 4 
     Cream 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
                 Stearic acid 
                 2.0 
               
               
                   
                 Stearyl alcohol 
                 7.0 
               
               
                   
                 Hydrous lanolin 
                 2.0 
               
               
                   
                 2-Octyldodecylalcohol 
                 6.0 
               
               
                   
                 Polyoxyethylene (25 mol) cetyl alcohol ether 
                 3.0 
               
               
                   
                 Glycerin monostearate ester 
                 2.0 
               
               
                   
                 2-O-dodecylascorbic acid 
                 2.0 
               
               
                   
                 2-O-octadecylascorbic acid 
                 2.0 
               
               
                   
                 1,3-Butylene glycol 
                 5.0 
               
               
                   
                 Trisodium edetate 
                 0.1 
               
               
                   
                 Sodium glycyrrhetinate 
                 0.1 
               
               
                   
                 Vitamin E acetate 
                 0.3 
               
               
                   
                 Ethylparaben 
                 0.3 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                   
               
            
           
         
       
     
     (Procedure) 
     2-O-dodecylascorbic acid, 2-O-octadecylascorbic acid, 1,3-butylene glycol, trisodium edetate and sodium glycyrrhetinate were added to the purified water and maintained at 70° C. to make an aqueous phase. On the other hand, other ingredients were heated with stirring, and melted then maintained at 70° C. to make an oil phase. The oil phase was added to the aqueous phase to pre-emulsify, then emulsified homogenously with a homomixer followed by cooling to 30° C. to obtain a cream. 
     Preparation Example 5 
     Emulsion 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Dimethyl polysiloxane 
                 3.0 
               
               
                   
                 Decamethylcyclopenta siloxane 
                 4.0 
               
               
                   
                 Ethanol 
                 5.0 
               
               
                   
                 Glycerin 
                 6.0 
               
               
                   
                 1,3-Butylene glycol 
                 5.0 
               
               
                   
                 2-O-dodecylascorbic acid 
                 0.5 
               
               
                   
                 2-O-octadecylascorbic acid 
                 0.5 
               
               
                   
                 Polyoxyethylene methyl glucoside 
                 3.0 
               
               
                   
                 Sunflower oil 
                 1.0 
               
               
                   
                 Squalene 
                 2.0 
               
               
                   
                 Potassium hydroxide 
                 0.1 
               
               
                   
                 Sodium hexametaphosphate 
                 0.05 
               
               
                   
                 Hydoxypropyl-β-cyclodextrin 
                 0.1 
               
               
                   
                 Potassium 4-methoxysalicilate 
                 1.0 
               
               
                   
                 Dipotassium glycyrrhizinate 
                 0.05 
               
               
                   
                 Loquat leaf extract 
                 0.1 
               
               
                   
                 Sodium L-glutamate 
                 0.05 
               
               
                   
                 Fennel extract 
                 0.1 
               
               
                   
                 Yeast extract 
                 0.1 
               
               
                   
                 Lavender oil 
                 0.1 
               
               
                   
                   Rehrnannia  root extract 
                 0.1 
               
               
                   
                 Dimorphorinopyridazinone 
                 0.1 
               
               
                   
                 Xanthan gum 
                 0.1 
               
               
                   
                 Carboxy vinyl polymer 
                 0.1 
               
               
                   
                 Alkyl acrylate/methacrylate copolymer 
                 0.1 
               
               
                   
                 (Pemulen TR-1) 
               
               
                   
                 Colcothar 
                 q.s. 
               
               
                   
                 Yellow iron oxide 
                 q.s. 
               
               
                   
                 Paraben 
                 q.s. 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                   
               
            
           
         
       
     
     Preparation Example 6 
     Emulsion 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Dimethyl polysiloxane 
                 3.0 
               
               
                   
                 Decamethylcyclopentasiloxane 
                 4.0 
               
               
                   
                 Ethanol 
                 5.0 
               
               
                   
                 Glycerin 
                 6.0 
               
               
                   
                 1,3-Butylene glycol 
                 5.0 
               
               
                   
                 2-O-octadecylascorbic acid 
                 1.0 
               
               
                   
                 Polyoxyethylene methyl glucoside 
                 3.0 
               
               
                   
                 Sunflower oil 
                 1.0 
               
               
                   
                 Squalene 
                 2.0 
               
               
                   
                 Potassium hydroxide 
                 0.1 
               
               
                   
                 Sodium hexametaphosphate 
                 0.05 
               
               
                   
                 Hydoxypropyl-β-cyclodextrin 
                 0.1 
               
               
                   
                 Potassium 4-methoxysalicilate 
                 1.0 
               
               
                   
                 Dipotassium glycyrrhizinate 
                 0.05 
               
               
                   
                 Loquat leaf extract 
                 0.1 
               
               
                   
                 Sodium L-glutamate 
                 0.05 
               
               
                   
                 Fennel extract 
                 0.1 
               
               
                   
                 Yeast extract 
                 0.1 
               
               
                   
                 Lavender oil 
                 0.1 
               
               
                   
                   Rehrnannia  root extract 
                 0.1 
               
               
                   
                 Dimorpholinopyridazinone 
                 0.1 
               
               
                   
                 Xanthan gum 
                 0.1 
               
               
                   
                 Carboxy vinyl polymer 
                 0.1 
               
               
                   
                 Alkyl acrylate/methacrylate copolymer 
                 0.1 
               
               
                   
                 (PemulenTR-1) 
               
               
                   
                 Colcothar 
                 q.s. 
               
               
                   
                 Yellow iron oxide 
                 q.s. 
               
               
                   
                 Paraben 
                 BR &gt; @ q.s. 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                   
               
            
           
         
       
     
     Preparation Example 7 
     Emulsion 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
                 Dimethyl polysiloxane 
                 2.0 
               
               
                   
                 Behenyl alcohol 
                 1.0 
               
               
                   
                 Batyl alcohol 
                 0.5 
               
               
                   
                 Glycerin 
                 5.0 
               
               
                   
                 1,3-Butylene glycol 
                 7.0 
               
               
                   
                 2-O-dodecylascorbic acid 
                 0.5 
               
               
                   
                 2-O-octadecylascorbic acid 
                 1.0 
               
               
                   
                 Tranexamic acid methylamide hydrochloride 
                 0.7 
               
               
                   
                 Erythritol 
                 2.0 
               
               
                   
                 Hydrogenated oil 
                 3.0 
               
               
                   
                 Squalene 
                 6.0 
               
               
                   
                 Pentaerythrit tetra 2-ethylhexanoate 
                 2.0 
               
               
                   
                 Polyoxyethylene glyceryl isostearate 
                 1.0 
               
               
                   
                 Polyoxyethylene glycerin monostearate 
                 1.0 
               
               
                   
                 Potassium hydroxide 
                 q.s. 
               
               
                   
                 Sodium hexametaphosphate 
                  0.05 
               
               
                   
                 Phenoxyethanol 
                 q.s. 
               
               
                   
                 Carboxy vinyl polymer 
                 0.1 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                   
               
            
           
         
       
     
     Preparation Example 8 
     Emulsion 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
                 Dimethyl polysiloxane 
                 2.0 
               
               
                   
                 Behenyl alcohol 
                 1.0 
               
               
                   
                 Batyl alcohol 
                 0.5 
               
               
                   
                 Glycerin 
                 5.0 
               
               
                   
                 1,3-Butylene glycol 
                 7.0 
               
               
                   
                 2-O-octadecylascorbic acid 
                 1.0 
               
               
                   
                 Tranexamic acid methylamide hydrochloride 
                 0.7 
               
               
                   
                 Erythritol 
                 2.0 
               
               
                   
                 Hydrogenated oil 
                 3.0 
               
               
                   
                 Squalene 
                 6.0 
               
               
                   
                 Pentaerythrit tetra 2-ethylhexanoate 
                 2.0 
               
               
                   
                 Polyoxyethylene glyceryl isostearate 
                 1.0 
               
               
                   
                 Polyoxyethylene glycerin monostearate 
                 1.0 
               
               
                   
                 Potassium hydroxide 
                 q.s. 
               
               
                   
                 Sodium hexametaphosphate 
                  0.05 
               
               
                   
                 Phenoxyethanol 
                 q.s. 
               
               
                   
                 Carboxy vinyl polymer 
                 0.1 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                   
               
            
           
         
       
     
     Preparation Example 9 
     Emulsion 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Liquid paraffin 
                 7.0 
               
               
                   
                 Vaseline 
                 3.0 
               
               
                   
                 Decamethylcyclopentasiloxane 
                 2.0 
               
               
                   
                 Behenyl alcohol 
                 0.5 
               
               
                   
                 Glycerin 
                 5.0 
               
               
                   
                 Dipropylene glycol 
                 7.0 
               
               
                   
                 2-O-dodecylascorbic acid 
                 1.0 
               
               
                   
                 2-O-octadecylascorbic acid 
                 1.0 
               
               
                   
                 Polyethylene glycol 1500 
                 2.0 
               
               
                   
                 Jojoba oil 
                 1.0 
               
               
                   
                 Isostearic acid 
                 0.5 
               
               
                   
                 Stearic acid 
                 0.5 
               
               
                   
                 Behenic acid 
                 0.5 
               
               
                   
                 Pentaerythrit tetra 2-ethylhexanoate 
                 3.0 
               
               
                   
                 Cetyl 2-ethylhexanoate 
                 3.0 
               
               
                   
                 Glycerin monostearate 
                 1.0 
               
               
                   
                 Polyoxyethylene glycerin monostearate 
                 1.0 
               
               
                   
                 Potassium hydroxide 
                 0.1 
               
               
                   
                 Sodium hexametaphosphate 
                 0.05 
               
               
                   
                 Stearyl glycyrrhetinate 
                 0.05 
               
               
                   
                 L-arginine hydrochloride 
                 0.1 
               
               
                   
                 Royal jelly extract 
                 0.1 
               
               
                   
                 Yeast extract 
                 0.1 
               
               
                   
                   Curcuma  extract 
                 0.1 
               
               
                   
                 Tocopherol acetate 
                 0.1 
               
               
                   
                 Acetylated sodium hyaluronate 
                 0.1 
               
               
                   
                 Trisodium edetate 
                 0.05 
               
               
                   
                 4-t-Butyl-4′-methoxydibenzoylmethan 
                 0.1 
               
               
                   
                 2-Ethylhexyl Para-methoxycinnamate 
                 0.1 
               
               
                   
                 Carboxy vinyl polymer 
                 0.15 
               
               
                   
                 Paraben 
                 q.s. 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                 Flavor 
                 q.s. 
               
               
                   
                   
               
            
           
         
       
     
     Preparation Example 10 
     Emulsion 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Vaseline 
                 5.0 
               
               
                   
                 Behenyl alcohol 
                 0.5 
               
               
                   
                 Batyl alcohol 
                 0.5 
               
               
                   
                 Glycerin 
                 7.0 
               
               
                   
                 1,3-Butylene glycol 
                 7.0 
               
               
                   
                 2-O-tridecylascorbic acid 
                 1.0 
               
               
                   
                 2-O-tetradecylascorbic acid 
                 1.0 
               
               
                   
                 1,2-pentanediol 
                 1.0 
               
               
                   
                 Xylit 
                 3.0 
               
               
                   
                 Polyethylene glycol 20000 
                 2.0 
               
               
                   
                 Hydrogenated oil 
                 2.0 
               
               
                   
                 Jojoba oil 
                 2.0 
               
               
                   
                 Squalene 
                 5.0 
               
               
                   
                 Isostearic acid 
                 0.5 
               
               
                   
                 Pentaerythrit tetra 2-ethylhexanoate 
                 2.0 
               
               
                   
                 Polyoxyethylene hydrogenated castor oil 
                 0.5 
               
               
                   
                 Lauryldimethylaminoacetic acid betaine 
                 0.4 
               
               
                   
                 Potassium hydroxide 
                 q.s. 
               
               
                   
                 Sodium pyrosulfite 
                 0.01 
               
               
                   
                 Sodium hexametaphosphate 
                 0.05 
               
               
                   
                 Dipotassium glycyrrhizinate 
                 0.05 
               
               
                   
                 Trimethylglycine 
                 3.0 
               
               
                   
                 Arbutin 
                 3.0 
               
               
                   
                   Pyrola japonica  extract 
                 0.1 
               
               
                   
                 Deadnettle extract 
                 0.1 
               
               
                   
                   Lempuyang  extract 
                 0.1 
               
               
                   
                 Yeast extract 
                 0.1 
               
               
                   
                 Tocopherol acetate 
                 0.1 
               
               
                   
                 Thiotaurine 
                 0.1 
               
               
                   
                   Clara  extract 
                 0.1 
               
               
                   
                 Colcothar 
                 q.s. 
               
               
                   
                 Qinceseed extract 
                 0.1 
               
               
                   
                 Carboxy vinyl polymer 
                 0.2 
               
               
                   
                 Phenoxyethanol 
                 q.s. 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                   
               
            
           
         
       
     
     Preparation Example 11 
     Emulsion 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Vaseline 
                 5.0 
               
               
                   
                 Dimethyl polysiloxane 
                 2.0 
               
               
                   
                 Behenyl alcohol 
                 0.6 
               
               
                   
                 Batyl alcohol 
                 0.5 
               
               
                   
                 Dipropylene glycol 
                 2.0 
               
               
                   
                 1,3-Butylene glycol 
                 4.0 
               
               
                   
                 2-O-pentadecylascorbic acid 
                 10.0 
               
               
                   
                 2-O-octadecylascorbic acid 
                 3.0 
               
               
                   
                 Xylit 
                 1.0 
               
               
                   
                 Polyethylene glycol 1500 
                 1.0 
               
               
                   
                 Squalene 
                 5.0 
               
               
                   
                 Glyceryl Tri2-ethylhexanoate 
                 2.0 
               
               
                   
                 Retinol acetate 
                 0.03 
               
               
                   
                 Retinol (1.5 million unit) 
                 0.01 
               
               
                   
                 Polyoxyethylene hydrogenated castor oil 
                 0.5 
               
               
                   
                 Tranexamic acid methylamide hydrochloride 
                 0.7 
               
               
                   
                 Dipotassium glycyrrhizinate 
                 0.1 
               
               
                   
                 2-O-ethyl-L-ascorbic acid 
                 0.1 
               
               
                   
                 Yeast extract 
                 0.1 
               
               
                   
                   Gambir  extract 
                 0.1 
               
               
                   
                   Peony  root extract 
                 0.1 
               
               
                   
                   Belamcanda  extract 
                 0.1 
               
               
                   
                 Trisodium HEDTA 
                 0.05 
               
               
                   
                 Xanthan gum 
                 0.1 
               
               
                   
                 Carboxy vinyl polymer 
                 0.15 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                 Flavor 
                 q.s. 
               
               
                   
                   
               
            
           
         
       
     
     Preparation Example 12 
     Lotion 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Ethylalcohol 
                 5.0 
               
               
                   
                 Glycerin 
                 1.0 
               
               
                   
                 1,3-Butylene glycol 
                 5.0 
               
               
                   
                 2-O-octadecylascorbic acid 
                 3.0 
               
               
                   
                 2-O-hexadecylascorbic acid 
                 10.0 
               
               
                   
                 Polyoxyethylene polyoxypropylene 
                 0.2 
               
               
                   
                 decyl tetradecyl ether 
               
               
                   
                 Sodium hexametaphosphate 
                 0.03 
               
               
                   
                 Trimethylglycine 
                 1.0 
               
               
                   
                 Sodium polyaspartate 
                 0.1 
               
               
                   
                 α-Tocopherol 2-L-ascorbate 
                 0.1 
               
               
                   
                 diesterpotassium phosphate 
               
               
                   
                 2-O-ethyl-L-ascorbic acid 
                 0.1 
               
               
                   
                 Green tea extract 
                 0.1 
               
               
                   
                 Beech extract 
                 0.1 
               
               
                   
                 Peach kernel 
                 0.1 
               
               
                   
                 Peppermint extract 
                 0.1 
               
               
                   
                 Iris root extract 
                 0.1 
               
               
                   
                 Trisodium HEDTA 
                 0.1 
               
               
                   
                 Carboxy vinyl polymer 
                 0.05 
               
               
                   
                 Potassium hydroxide 
                 0.02 
               
               
                   
                 Phenoxyethanol 
                 q.s. 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                 Flavor 
                 q.s. 
               
               
                   
                   
               
            
           
         
       
     
     Preparation Example 13 
     Lotion 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Glycerin 
                 2.0 
               
               
                   
                 1,3-Butylene glycol 
                 4.0 
               
               
                   
                 2-O-heptadecylascorbic acid 
                 1.0 
               
               
                   
                 2-O-octadecylascorbic acid 
                 1.0 
               
               
                   
                 Erythritol 
                 1.0 
               
               
                   
                 Polyoxyethylene methylglucoside 
                 1.0 
               
               
                   
                 Polyoxyethylene hydrogenated castor oil 
                 0.5 
               
               
                   
                 L-ascorbic acid 2-glucoside 
                 2.0 
               
               
                   
                 Xylitol 
                 0.1 
               
               
                   
                 Citric acid 
                 0.02 
               
               
                   
                 Sodium citric acid 
                 0.08 
               
               
                   
                 Phenoxyethanol 
                 q.s. 
               
               
                   
                 N-coconut oil fatty acid acyl L-arginine ethyl/ 
                 0.1 
               
               
                   
                 DL-pyrrolidone carboxylic acid 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                   
               
            
           
         
       
     
     Preparation Example 14 
     Lotion 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Glycerin 
                 2.0 
               
               
                   
                 1,3-Butylene glycol 
                 4.0 
               
               
                   
                 2-O-dodecylascorbic acid 
                 1.0 
               
               
                   
                 2-O-octadecylascorbic acid 
                 1.0 
               
               
                   
                 Erythritol 
                 1.0 
               
               
                   
                 Polyoxyethylene methylglucoside 
                 1.0 
               
               
                   
                 Polyoxyethylene hydrogenated castor oil 
                 0.5 
               
               
                   
                 L-ascorbic acid 2-glucoside 
                 2.0 
               
               
                   
                 Xylitol 
                 0.1 
               
               
                   
                 Citric acid 
                 0.02 
               
               
                   
                 Sodium citric acid 
                 0.08 
               
               
                   
                 Phenoxyethanol 
                 q.s. 
               
               
                   
                 N-coconut oil fatty acid acyl L-arginine ethyl/ 
                 0.1 
               
               
                   
                 DL-pyrrolidone carboxylic acid 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                   
               
            
           
         
       
     
     Preparation Example 15 
     Lotion 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Ethanol 
                 10.0 
               
               
                   
                 Dipropylene glycol 
                 1.0 
               
               
                   
                 Sodium 2-O-dodecylascorbate 
                 1.0 
               
               
                   
                 Sodium 2-O-tridecylascorbate 
                 1.0 
               
               
                   
                 Polyethylene glycol 1000 
                 1.0 
               
               
                   
                 Polyoxyethylene methylglucoside 
                 1.0 
               
               
                   
                 Jojoba oil 
                 0.01 
               
               
                   
                 Glyceryl tri2-ethylhexanate 
                 0.1 
               
               
                   
                 Polyoxyethylene hydrogenated castor oil 
                 0.2 
               
               
                   
                 Polyglyceryl diisostearate 
                 0.15 
               
               
                   
                 Sodium N-stearoil-L-glutamate 
                 0.1 
               
               
                   
                 Citric acid 
                 0.05 
               
               
                   
                 Sodium citric acid 
                 0.2 
               
               
                   
                 Potassium hydroxide 
                 0.4 
               
               
                   
                 Dipotassium glycyrrhizinate 
                 0.1 
               
               
                   
                 Arginine hydrochloride 
                 0.1 
               
               
                   
                 L-ascorbic acid 2-glucoside 
                 2.0 
               
               
                   
                   Scutellaria  extract 
                 0.1 
               
               
                   
                   Saxifraga stolonifera  extract 
                 0.1 
               
               
                   
                 Deadnettle extract 
                 0.1 
               
               
                   
                 Thyme extract 
                 0.1 
               
               
                   
                   Origanum majorana  extract 
                 0.1 
               
               
                   
                 Tranexamic acid 
                 1.0 
               
               
                   
                 Trisodium edetate 
                 0.05 
               
               
                   
                 2-Ethylhexyl para-methoxycinnamate 
                 0.01 
               
               
                   
                 Dibutylhydroxytoluene 
                 q.s. 
               
               
                   
                 Paraben 
                 q.s. 
               
               
                   
                 Ocean deep water 
                 3.0 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                 Flavor 
                 q.s. 
               
               
                   
                   
               
            
           
         
       
     
     Preparation Example 16 
     Lotion 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
                 Dimethyl polysiloxane 
                 1.0 
               
               
                   
                 Ethanol 
                 3.0 
               
               
                   
                 Behenyl alcohol 
                 0.3 
               
               
                   
                 Glycerin 
                 5.0 
               
               
                   
                 Dipropylene glycol 
                 5.0 
               
               
                   
                 2-O-tetradecylascorbic acid 
                 0.1 
               
               
                   
                 2-O-octadecylascorbic acid 
                 0.1 
               
               
                   
                 Erythritol 
                 1.0 
               
               
                   
                 Polyethylene glycol 4000 
                 1.0 
               
               
                   
                 Squalene 
                 0.4 
               
               
                   
                 Cetyl 2-ethylhexanoate 
                 0.1 
               
               
                   
                 Sodium N-stearoyl-L-glutamate 
                 0.2 
               
               
                   
                 Magnesium chloride 
                 0.1 
               
               
                   
                 Arginine chloride 
                 0.1 
               
               
                   
                 Hypotaurine 
                 0.1 
               
               
                   
                 Trisodium edetate 
                 0.1 
               
               
                   
                 Paraben 
                 q.s. 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                 Flavor 
                 q.s. 
               
               
                   
                   
               
            
           
         
       
     
     Preparation Example 17 
     Lotion 
       
     
       
         
           
               
               
             
               
                   
               
               
                 (Formulation) 
                 % by mass 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 Ethanol 
                 40.0 
               
               
                 Dipropylene glycol 
                 1.0 
               
               
                 2-O-dodecylascorbic acid 
                 0.1 
               
               
                 2-O-pentadecylascorbic acid 
                 0.1 
               
               
                 Polyoxyethylene polyoxypropylene decyl tetradecyl ether 
                 0.1 
               
               
                 Anhydrous silicic acid 
                 1.0 
               
               
                 Salicylic acid 
                 0.1 
               
               
                 Sodium citrate 
                 0.2 
               
               
                 Zinc paraphenolsulfonate 
                 0.2 
               
               
                 Dipotassium glycyrrhizinate 
                 0.1 
               
               
                 Pyridoxine hydrochloride 
                 0.1 
               
               
                 L-Serine 
                 0.1 
               
               
                 L-Menthol 
                 0.05 
               
               
                 Trisodium HEDTA 
                 0.05 
               
               
                 Powdered cellulose 
                 1.0 
               
               
                 Bentonite 
                 0.8 
               
               
                 Purified water 
                 balance 
               
               
                   
               
            
           
         
       
     
     Preparation Example 18 
     Lotion 
       
     
       
         
           
               
               
             
               
                   
               
               
                 (Formulation) 
                 % by mass 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 Ethanol 
                 40.0 
               
               
                 Dipropylene glycol 
                 1.0 
               
               
                 Potassium 2-O-octadecylascorbate 
                 0.1 
               
               
                 Polyoxyethylene polyoxypropylene decyl tetradecyl ether 
                 0.1 
               
               
                 Anhydrous silicic acid 
                 1.0 
               
               
                 Salicylic acid 
                 0.1 
               
               
                 Sodium citrate 
                 0.2 
               
               
                 Zinc paraphenolsulfonate 
                 0.2 
               
               
                 Dipotassium glycyrrhizinate 
                 0.1 
               
               
                 Pyridoxine hydrochloride 
                 0.1 
               
               
                 L-Serine 
                 0.1 
               
               
                 L-Menthol 
                 0.05 
               
               
                 Trisodium HEDTA 
                 0.05 
               
               
                 Powdered cellulose 
                 1.0 
               
               
                 Bentonite 
                 0.8 
               
               
                 Purified water 
                 balance 
               
               
                   
               
            
           
         
       
     
     Preparation Example 19 
     Gel 
       
     
       
         
           
               
               
             
               
                   
               
               
                 (Formulation) 
                 % by mass 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 Dimethyl polysiloxane 
                 5.0 
               
               
                 Glycerin 
                 2.0 
               
               
                 1,3-Butylene glycol 
                 5.0 
               
               
                 2-O-dodecylascorbic acid 
                 0.1 
               
               
                 2-O-octadecylascorbic acid 
                 0.1 
               
               
                 Polyethylene glycol 1500 
                 3.0 
               
               
                 Polyethylene glycol 20000 
                 3.0 
               
               
                 Cetyl octanoate 
                 3.0 
               
               
                 Citric acid 
                 0.01 
               
               
                 Sodium citrate 
                 0.1 
               
               
                 Sodium hexametaphosphate 
                 0.1 
               
               
                 Dipotassium glycyrrhizinate 
                 0.1 
               
               
                 L-ascorbic acid 2-glucoside 
                 2.0 
               
               
                 Magnesium L-ascorbate phosphate 
                 0.1 
               
               
                 Tocopherol acetate 
                 0.1 
               
               
                   Scutellaria  extract 
                 0.1 
               
               
                 Thime extract 
                 0.1 
               
               
                 Strawberry geranium extract 
                 0.1 
               
               
                 Trisodium edetate 
                 0.1 
               
               
                 Xanthan gum 
                 0.3 
               
               
                 Alkyl acrylate/methacrylate copolymer (PemulenTR-2) 
                 0.05 
               
               
                 Powdered agar 
                 1.5 
               
               
                 Phenoxyethanol 
                 q.s. 
               
               
                 Dibutylhydrokytoluene 
                 q.s. 
               
               
                 Purified water 
                 balance 
               
               
                   
               
            
           
         
       
     
     Preparation Example 20 
     Pack 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Ethanol 
                 10.0 
               
               
                   
                 1,3-Butylene glycol 
                 6.0 
               
               
                   
                 2-O-dodecylascorbic acid 
                 1.0 
               
               
                   
                 2-O-octadecylascorbic acid 
                 1.0 
               
               
                   
                 Polyethylene glycol 4000 
                 2.0 
               
               
                   
                 Olive oil 
                 1.0 
               
               
                   
                   Macadamia  nuts oil 
                 1.0 
               
               
                   
                 Phytosteryl hydroxystearate 
                 0.05 
               
               
                   
                 Lactic acid 
                 0.05 
               
               
                   
                 Sodium lactate 
                 0.1 
               
               
                   
                 L-Ascorbic acid disodium sulfate 
                 0.1 
               
               
                   
                 α-Tocopherol 2-L-ascorbate dipotassium phosphate 
                 0.1 
               
               
                   
                 Vitamin E acetate 
                 0.1 
               
               
                   
                 Fish collagen 
                 0.1 
               
               
                   
                 Sodium chondroitin sulfate 
                 0.1 
               
               
                   
                 Sodium carboxymethylcellulose 
                 0.2 
               
               
                   
                 Polyvinyl alcohol 
                 12.0 
               
               
                   
                 Para-oxybenzoic acid ester 
                 q.s. 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                 Flavor 
                 q.s. 
               
               
                   
                   
               
            
           
         
       
     
     Preparation Example 21 
     Pack 
       
     
       
         
           
               
               
             
               
                   
               
               
                 (Formulation) 
                 % by mass 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 Ethanol 
                 3.0 
               
               
                 Glycerin 
                 5.0 
               
               
                 1,3-Butylene glycol 
                 6.0 
               
               
                 2-O-octadecylascorbic acid 
                 1.0 
               
               
                 2-O-hexadecylascorbic acid 
                 1.0 
               
               
                 Polyethylene glycol 1500 
                 5.0 
               
               
                 Polyoxyethylenemethylglucoside 
                 2.0 
               
               
                 Glyceryl tri2-ethylhexanoate 
                 1.0 
               
               
                 Sodium hexametaphosphate 
                 0.05 
               
               
                 Hydroxypropyl-β-cyclodextrin 
                 0.1 
               
               
                 Dipotassium glycyrrhizinate 
                 0.1 
               
               
                   Loquat  leaf extract 
                 0.1 
               
               
                 Sodium L-glutamate 
                 0.1 
               
               
                   Foeniculum vulgare  extract 
                 0.1 
               
               
                   Hamamelis japonica  extract 
                 0.1 
               
               
                   Phellodendron bark  extract 
                 0.1 
               
               
                   Rehmannia glutinosa  extract 
                 0.1 
               
               
                   Eucalyptus  oil 
                 0.05 
               
               
                 Dimorpholinopyridazinone 
                 0.1 
               
               
                 Xanthan gum 
                 0.05 
               
               
                 Carboxy vinyl polymer 
                 0.5 
               
               
                 Acrylic acid/alkyl methacrylate copolymer (Pemulen TR-1) 
                 0.05 
               
               
                 Potassium hydroxide 
                 0.05 
               
               
                 Phenoxyethanol 
                 q.s. 
               
               
                 Purified water 
                 balance 
               
               
                   
               
            
           
         
       
     
     Preparation Example 22 
     Pack 
       
     
       
         
           
               
               
             
               
                   
               
               
                 (Formulation) 
                 % by mass 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 Ethanol 
                 3.0 
               
               
                 Glycerin 
                 5.0 
               
               
                 1,3-Butylene glycol 
                 6.0 
               
               
                 2-O-octadecylascorbic acid 
                 1.0 
               
               
                 Polyethylene glycol 1500 
                 5.0 
               
               
                 Polyoxyethylenemethylglucoside 
                 2.0 
               
               
                 Glyceryl tri2-ethylhexanoate 
                 1.0 
               
               
                 Sodium hexametaphosphate 
                 0.05 
               
               
                 Hydroxypropyl-β-cyclodextrin 
                 0.1 
               
               
                 Dipotassium glycyrrhizinate 
                 0.1 
               
               
                 Loquat leaf extract 
                 0.1 
               
               
                 Sodium L-glutamate 
                 0.1 
               
               
                   Foeniculum vulgare  extract 
                 0.1 
               
               
                   Hamamelis japonica  extract 
                 0.1 
               
               
                   Phellodendron bark  extract 
                 0.1 
               
               
                   Rehmannia glutinosa  extract 
                 0.1 
               
               
                   Eucalyptus  oil 
                 0.05 
               
               
                 Dimorpholinopyridazinone 
                 0.1 
               
               
                 Xanthan gum 
                 0.05 
               
               
                 Carboxy vinyl polymer 
                 0.5 
               
               
                 Acrylic acid/alkyl methacrylate copolymer (Pemulen TR-1) 
                 0.05 
               
               
                 Potassium hydroxide 
                 0.05 
               
               
                 Phenoxyethanol 
                 q.s. 
               
               
                 Purified water 
                 balance 
               
               
                   
               
            
           
         
       
     
     Preparation Example 23 
     Cream 
       
     
       
         
           
               
               
             
               
                   
               
               
                 (Formulation) 
                 % by mass 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 Liquid paraffin 
                 3.0 
               
               
                 Vaseline 
                 1.0 
               
               
                 Dimethylpolysiloxane 
                 1.0 
               
               
                 Stearyl alcohol 
                 1.8 
               
               
                 Behenyl alcohol 
                 1.6 
               
               
                 Glycerin 
                 8.0 
               
               
                 Dipropylene glycol 
                 5.0 
               
               
                 2-O-octadecylascorbic acid 
                 5.0 
               
               
                 2-O-dodecylascorbic acid 
                 5.0 
               
               
                   Macadamia  nuts oil 
                 2.0 
               
               
                 Hydrogenated oil 
                 3.0 
               
               
                 Squalan 
                 6.0 
               
               
                 Stearic acid 
                 2.0 
               
               
                 Cholesteryl hydroxystearate 
                 0.5 
               
               
                 Cetyl 2-ethylhexanoate 
                 4.0 
               
               
                 Polyoxyethylene hydrogenated castor oil 
                 0.5 
               
               
                 Self emulsification type glycerin monostearate 
                 3.0 
               
               
                 Potassium hydroxide 
                 0.15 
               
               
                 Sodium hexametaphosphate 
                 0.05 
               
               
                 Trimethylglycine 
                 2.0 
               
               
                 α-Tocopherol 2-L-ascorbate diesterpotassium phosphate 
                 1.0 
               
               
                 Tocopherol acetate 
                 0.1 
               
               
                 Tencha extract 
                 0.1 
               
               
                 Paraben 
                 q.s. 
               
               
                 Trisodium edetate 
                 0.05 
               
               
                 4-t-Butyl-4′-methoxybenzoylmethane 
                 0.05 
               
               
                 Glyceryl dipara-methoxycinnamate mono-2-ethylhexanoate 
                 0.05 
               
               
                 Colorant 
                 q.s. 
               
               
                 Carboxy vinyl polymer 
                 0.05 
               
               
                 Purified water 
                 balance 
               
               
                   
               
            
           
         
       
     
     Preparation Example 24 
     Cream 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Liquid paraffin 
                 8.0 
               
               
                   
                 Vaseline 
                 3.0 
               
               
                   
                 Dimethylpolysiloxane 
                 2.0 
               
               
                   
                 Stearyl alcohol 
                 3.0 
               
               
                   
                 Behenyl alcohol 
                 2.0 
               
               
                   
                 Glycerin 
                 5.0 
               
               
                   
                 Dipropylene glycol 
                 4.0 
               
               
                   
                 2-O-heptadecylascorbic acid 
                 3.0 
               
               
                   
                 2-O-octadecylascorbic acid 
                 3.0 
               
               
                   
                 Trehalose 
                 1.0 
               
               
                   
                 Pentaerythrit tetra2-ethylhexanoate 
                 4.0 
               
               
                   
                 Polyoxyethyleneglyceryl monoisostearate 
                 2.0 
               
               
                   
                 Polyoxyethyleneglycerin monostearate 
                 1.0 
               
               
                   
                 Lipophilic type glycerin monostearate 
                 2.0 
               
               
                   
                 Citric acid 
                 0.05 
               
               
                   
                 Sodium citrate 
                 0.05 
               
               
                   
                 Potassium hydroxide 
                 0.015 
               
               
                   
                 Oil soluble  Glycyrrhiza  extract 
                 0.1 
               
               
                   
                 Retinol palmitate (a million units) 
                 0.25 
               
               
                   
                 Tocopherol acetate 
                 0.1 
               
               
                   
                 Para-oxybenzoic acid ester 
                 q.s. 
               
               
                   
                 Phenoxyethanol 
                 q.s. 
               
               
                   
                 Dibutylhydroxytoluene 
                 q.s. 
               
               
                   
                 Trisodium edetate 
                 0.05 
               
               
                   
                 4-t-Butyl-4′-methoxybenzoylmethane 
                 0.01 
               
               
                   
                 2-Ethylhexyl para-methoxycinnamate 
                 0.1 
               
               
                   
                 β-Carotene 
                 0.01 
               
               
                   
                 Polyvinyl alcohol 
                 0.5 
               
               
                   
                 Hydroxyethylcellulose 
                 0.5 
               
               
                   
                 Carboxy vinyl polymer 
                 0.05 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                 Flavor 
                 q.s. 
               
               
                   
                   
               
            
           
         
       
     
     Preparation Example 25 
     Cream 
       
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 (Formulation) 
                 % by mass 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Liquid paraffin 
                 8.0 
               
               
                   
                 Vaseline 
                 3.0 
               
               
                   
                 Dimethylpolysiloxane 
                 2.0 
               
               
                   
                 Stearyl alcohol 
                 3.0 
               
               
                   
                 Behenyl alcohol 
                 2.0 
               
               
                   
                 Glycerin 
                 5.0 
               
               
                   
                 Dipropylene glycol 
                 4.0 
               
               
                   
                 2-O-octadecylascorbic acid 
                 3.0 
               
               
                   
                 Trehalose 
                 1.0 
               
               
                   
                 Pentaerythrit tetra2-ethylhexanoate 
                 4.0 
               
               
                   
                 Polyoxyethyleneglyceryl monoisostearate 
                 2.0 
               
               
                   
                 Polyoxyethyleneglycerin monostearate 
                 1.0 
               
               
                   
                 Lipophilic type glycerin monostearate 
                 2.0 
               
               
                   
                 Citric acid 
                 0.05 
               
               
                   
                 Sodium citrate 
                 0.05 
               
               
                   
                 Potassium hydroxide 
                 0.015 
               
               
                   
                 Oil soluble  Glycyrrhiza  extract 
                 0.1 
               
               
                   
                 Retinol palmitate (a million units) 
                 0.25 
               
               
                   
                 Tocopherol acetate 
                 0.1 
               
               
                   
                 Para-oxybenzoic acid ester 
                 q.s. 
               
               
                   
                 Phenoxyethanol 
                 q.s. 
               
               
                   
                 Dibutylhydroxytoluene 
                 q.s. 
               
               
                   
                 Trisodium edetate 
                 0.05 
               
               
                   
                 4-t-Butyl-4′-methoxybenzoylmethane 
                 0.01 
               
               
                   
                 2-Ethylhexyl para-methoxycinnamate 
                 0.1 
               
               
                   
                 β-Carotene 
                 0.01 
               
               
                   
                 Polyvinyl alcohol 
                 0.5 
               
               
                   
                 Hydroxyethylcellulose 
                 0.5 
               
               
                   
                 Carboxy vinyl polymer 
                 0.05 
               
               
                   
                 Purified water 
                 balance 
               
               
                   
                 Flavor 
                 q.s. 
               
               
                   
                   
               
            
           
         
       
     
     Preparation Example 26 
     Cream 
       
     
       
         
           
               
               
             
               
                   
               
               
                 (Formulation) 
                 % by mass 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 Vaseline 
                 2.0 
               
               
                 Dimethylpolysiloxane 
                 2.0 
               
               
                 Ethanol 
                 5.0 
               
               
                 Behenyl alcohol 
                 0.5 
               
               
                 Batyl alcohol 
                 0.2 
               
               
                 Glycerin 
                 7.0 
               
               
                 1,3-Butylene glycol 
                 5.0 
               
               
                 2-O-dodecylascorbic acid 
                 1.0 
               
               
                 2-O-octadecylascorbic acid 
                 1.0 
               
               
                 Polyethylene glycol 20000 
                 0.5 
               
               
                 Jojoba oil 
                 3.0 
               
               
                 Squalan 
                 2.0 
               
               
                 Phytosteryl hydroxystearate 
                 0.5 
               
               
                 Pentaerythrit tetra2-ethylhexanoate 
                 1.0 
               
               
                 Polyoxyethylene hydrogenated castor oil 
                 1.0 
               
               
                 Potassium hydroxide 
                 0.1 
               
               
                 Sodium pyrosulfite 
                 0.01 
               
               
                 Sodium hexametaphosphate 
                 0.05 
               
               
                 Stearyl glycyrrhizinate 
                 0.1 
               
               
                 Pantothenyl ethyl ether 
                 0.1 
               
               
                 Albutin 
                 7.0 
               
               
                 Tranexamic acid 
                 1.0 
               
               
                 Tocopherol acetate 
                 0.1 
               
               
                 Sodium hyaluronate 
                 0.05 
               
               
                 Para-oxybenzoic acid ester 
                 q.s. 
               
               
                 Trisodium edetate 
                 0.05 
               
               
                 4-t-Butyl-4′-methoxybenzoylmethane 
                 0.1 
               
               
                 Mono 2-ethylhexanoate glyceryl dipara-methoxycinnamate 
                 0.1 
               
               
                 Yellow iron oxide 
                 q.s. 
               
               
                 Xantan gum 
                 0.1 
               
               
                 Carboxy vinyl polymer 
                 0.2 
               
               
                 Purified water 
                 balance 
               
               
                   
               
            
           
         
       
     
     Preparation Example 27 
     Cream 
       
     
       
         
           
               
               
             
               
                   
               
               
                 (Formulation) 
                 % by mass 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 Liquid paraffin 
                 10.0 
               
               
                 Dimethylpolysiloxane 
                 2.0 
               
               
                 Glycerin 
                 10.0 
               
               
                 1,3-Butylene glycol 
                 2.0 
               
               
                 2-O-dodecylascorbic acid 
                 1.0 
               
               
                 2-O-octadecylascorbic acid 
                 1.0 
               
               
                 Erythritol 
                 1.0 
               
               
                 Polyethylene glycol 1500 
                 5.0 
               
               
                 Squalan 
                 15.0 
               
               
                 Pentaerythrit tetra2-ethylhexanoate 
                 5.0 
               
               
                 Potassium hydroxide 
                 0.1 
               
               
                 Sodium hexametaphosphate 
                 0.05 
               
               
                 Tocopherol acetate 
                 0.05 
               
               
                 Para-oxybenzoic acid ester 
                 q.s. 
               
               
                 Hydroxypropylmethylcellulose 
                 0.3 
               
               
                 Polyvinyl alcohol 
                 0.1 
               
               
                 Carboxy vinyl polymer 
                 0.2 
               
               
                 Acrylic acid/alkyl methacrylate copolymer (Pemulen TR-2) 
                 0.1 
               
               
                 Purified water 
                 balance 
               
               
                   
               
            
           
         
       
     
     Preparation Example 28 
     Cream 
       
     
       
         
           
               
               
             
               
                   
               
               
                 (Formulation) 
                 % by mass 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 Liquid paraffin 
                 10.0 
               
               
                 Dimethylpolysiloxane 
                 2.0 
               
               
                 Glycerin 
                 10.0 
               
               
                 1,3-Butylene glycol 
                 2.0 
               
               
                 2-O-octadecylascorbic acid 
                 1.0 
               
               
                 Erythritol 
                 1.0 
               
               
                 Polyethylene glycol 1500 
                 5.0 
               
               
                 Squalan 
                 15.0 
               
               
                 Pentaerythrit tetra2-ethylhexanoate 
                 5.0 
               
               
                 Potassium hydroxide 
                 0.1 
               
               
                 Sodium hexametaphosphate 
                 0.05 
               
               
                 Tocopherol acetate 
                 0.05 
               
               
                 Para-oxybenzoic acid ester 
                 q.s. 
               
               
                 Hydroxypropylmethylcellulose 
                 0.3 
               
               
                 Polyvinyl alcohol 
                 0.1 
               
               
                 Carboxy vinyl polymer 
                 0.2 
               
               
                 Acrylic acid/alkyl methacrylate copolymer (Pemulen TR-2) 
                 0.1 
               
               
                 Purified water 
                 balance 
               
               
                   
               
            
           
         
       
     
     Preparation Example 29 
     Two-Layer Cream 
       
     
       
         
           
               
               
             
               
                   
               
               
                 (Formulation) 
                 % by mass 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 Dimethylpolysiloxane 
                 5.0 
               
               
                 Decamethylcyclopentasiloxane 
                 25.0 
               
               
                 Trimethylsiloxy silicate 
                 5.0 
               
               
                 Polyoxyethylene/methylpolysiloxane copolymer 
                 2.0 
               
               
                 Dipropylene glycol 
                 5.0 
               
               
                 2-O-dodecylascorbic acid 
                 0.01 
               
               
                 2-O-octadecylascorbic acid 
                 0.01 
               
               
                 Dextrin palmitate-coating particle zinc oxide (60 nm) 
                 15.0 
               
               
                 Dipotassium glycyrrhizinate 
                 0.02 
               
               
                 Glutathione 
                 1.0 
               
               
                 Thiotaurine 
                 0.05 
               
               
                 Clara extract 
                 1.0 
               
               
                 Paraben 
                 q.s. 
               
               
                 Phenoxyethanol 
                 q.s. 
               
               
                 Trisodium edetate 
                 q.s. 
               
               
                 2-Ethylhexyl para-methoxycinnamate 
                 7.5 
               
               
                 Dimethyldistearylammonium hectright 
                 0.5 
               
               
                 Spherical alkyl polycrylate powder 
                 5.0 
               
               
                 Butylethylpropane diol 
                 0.5 
               
               
                 Purified water 
                 balance 
               
               
                 Flavor 
                 q.s. 
               
               
                   
               
            
           
         
       
     
     Any injection or dermatological external agents of the preparation Examples 1-29 described above had high ADAM inhibiting effect.