Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/63—Steroids; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/16—Emollients or protectives, e.g. against radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin

Definitions

• the present invention relates to a composition for skin whitening, and more particularly, skin whitening including platicodine-D, which has excellent product stability, can be safely used without side effects on the skin, and inhibits melanin production and has excellent pigmentation inhibitory effect.
• Human skin color is determined by the concentration and distribution of melanin in the skin. In addition to genetic factors, it is also influenced by environmental or physiological conditions such as sun ultraviolet rays, fatigue and stress.
• Melanin pigment produced by melanocytes of human skin is a phenolic polymer having a complex form of black pigment and protein, and plays an important role in preventing skin damage caused by ultraviolet rays. In melanin biosynthesis, the action of tyrosinase in melanocytes is reported to be the most important. Tyrosinase plays a key role in the skin blackening process by converting tyrosine, an amino acid, into dopa and dopaquinone, intermediates of melanin polymer production. However, although the pathway by which melanin is made is known, it is still not clear what mechanisms induce melanin synthesis, the previous step in which tyrosinase works.
• substances having inhibitory activity against tyrosinase such as hydroquinone, ascorbic acid, kojic acid, and glutathione are used to prevent skin whitening or hyperpigmentation.
• hydroquinone exhibits a predetermined whitening effect but severe skin irritation has a problem of limiting the blending amount to a very small amount.
• Ascorbic acid is easily oxidized, and the cosmetics containing it are discolored and discolored. Acid is unstable in solution, which complicates the manufacturing process of cosmetics.
• thiol-based compounds such as glutathione and cysteine not only have a characteristic unpleasant odor, but also have problems with transdermal absorption, and glycosides and derivatives thereof have high polarity, making it difficult to use as a cosmetic ingredient.
• vitamin C has a problem in that it is easily oxidized in the aqueous solution state does not have a continuous effect. Accordingly, in recent years, compositions for skin whitening including natural herbal extracts have been developed, but most of them have color problems, and there is a problem in formulation, and the active ingredients have not been identified, and thus there is a problem in that the same effect cannot be expected when manufacturing products.
• Platycodin-D is one of the triterpenoid saponin compounds present in the roots of bellflower, and has been reported to have anti-inflammatory, anti-obesity, cholesterol-lowering effects, and analgesic inhibitory effects.
• US Patent Application No. 2002/0197334 discloses that platicodine-di has an effect on diabetes, and WO 2005/007181 discloses that it has an effect of inhibiting cancer through a mechanism of inhibiting neovascular production. Doing. As such, various studies on the efficacy of the natural substance platicodine-D have been made.
• One object of the present invention relates to a cosmetic composition for skin whitening comprising platicodine-di.
• Another object of the present invention relates to a pharmaceutical composition for skin whitening comprising platicodine-di.
• Another object of the present invention relates to a method for whitening skin by applying the composition to the skin of a mammal, including humans.
• platicodine-D has a higher inhibitory effect on intracellular tyrosinase and a melanin production inhibitory effect than vitamin C, which is a main component of the existing whitening agent.
• vitamin C which is a main component of the existing whitening agent.
• the present invention relates to a cosmetic composition for skin whitening comprising Platycodin D.
• Platycodin-D (platycodin-D) of the present invention is a kind of triterpenoid saponin derived from plants having the structure of the following formula (1).
• Platicodin-di of the present invention may be prepared from chemical modifications, or by chemical modification of triterpenoid saponins isolated from natural sources (eg, bellflower, etc.), or obtained from natural sources. Or a commercially prepared product (eg, Platycodin D from Pharmavan).
• the platicodine-di of the present invention can be extracted and separated at 0 ° C. to 50 ° C. using a solvent such as water, alcohol or acetone at the root of bellflower, and such extraction and separation methods are available to those skilled in the art. It is well known.
• the platicodine-D of the present invention In order to examine the whitening effect of the platicodine-D of the present invention, compared with vitamin C (vitamin C), which is used as a conventional whitening cosmetic raw material, intracellular tyrosinase activity and melanin production inhibitory effect generally used for screening whitening substances As a result, at the same concentration, the platycodine-diga of the present invention was superior to the inhibitory effect of tyrosinase activity and melanogenesis by about 10% or more than vitamin C. Therefore, the platicodine-di of the present invention is excellent in the whitening effect.
• vitamin C vitamin C
• Platicodin-D of the formula (1) of the present invention derivatives exhibiting a skin whitening effect by inhibiting melanin production and / or tyrosinase activity of the derivatives obtained by the addition or substitution reaction of substituents commonly practiced in the art It is clear to those skilled in the art in consideration of the level of skill in the art.
• the amount of platicodine-di in the cosmetic composition for skin whitening of the present invention is preferably 0.001 to 10% by weight, preferably 0.001 to 5% by weight based on the total composition. If it is less than 0.001% by weight, the whitening effect is too weak, and if it exceeds 15% by weight, there is a problem that the increase in effect due to the increase of the content is insufficient and the stability of the formulation is not secured.
• the cosmetic composition for skin whitening of the present invention may include components conventionally used in cosmetic compositions in addition to Platicodin-D as an active ingredient.
• components conventionally used in cosmetic compositions in addition to Platicodin-D as an active ingredient.
• auxiliaries and / or carriers such as antioxidants, stabilizers, solubilizers, vitamins, pigments and flavorings.
• the cosmetic composition may further include a skin absorption promoting material to enhance the skin whitening effect.
• Cosmetic compositions of the present invention can be prepared in any formulation conventionally prepared in the art, for example, solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, surfactant-containing cleansing , Oils, powder foundations, emulsion foundations, wax foundations and sprays, and the like, but are not limited thereto. More preferably, it may be prepared in the form of a flexible lotion, nutrition lotion, nutrition cream, massage cream, essence, eye cream, cleansing cream, cleansing foam, cleansing water, pack, spray or powder.
• the formulation of the present invention is a paste, cream or gel, animal oils, vegetable oils, waxes, paraffins, starches, trachants, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicas, talc or zinc oxide may be used as carrier components.
• animal oils, vegetable oils, waxes, paraffins, starches, trachants, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicas, talc or zinc oxide may be used as carrier components.
• animal oils vegetable oils, waxes, paraffins, starches, trachants, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicas, talc or zinc oxide
• cellulose derivatives polyethylene glycols
• silicones bentonites
• silicas talc or zinc oxide
• lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used, in particular in the case of a spray, additionally chlorofluorohydrocarbon, propane Propellant such as butane or dimethyl ether.
• a solvent, solubilizer or emulsifier is used as the carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 Fatty acid esters of, 3-butylglycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan.
• liquid carrier diluents such as water, ethanol or propylene glycol
• suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystals Soluble cellulose, aluminum metahydroxy, bentonite, agar or tracant and the like can be used.
• the carrier component is aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide.
• Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters and the like can be used.
• the present invention relates to a pharmaceutical composition for skin whitening comprising Platycodin D.
• the amount of platicodine-di may comprise 0.001 to 10% by weight, preferably 0.001 to 5% by weight based on the total composition.
• the pharmaceutical composition may be formulated as a conventional agent in the pharmaceutical field according to the therapeutic purpose, for example, tablets, capsules, powders, granules, suspensions, emulsions, syrups, emulsions, warnings, ointments, sprays , Oils, gels, spirits, tinctures, baths, linings, lotions, patches, pads, creams and the like.
• the topical skin preparation for topical administration directly applied to the affected area is in the form of an ointment, lotion, spray, gel or the like.
• These dermal external preparations may also be included in support bases or matrices that may be applied directly to the treatment site, and examples of the support bases include gauze or bandages.
• the pharmaceutical composition used in the formulation may be in colloidal form or dried powder form or the like.
• the skin surface temperature, skin pH, transdermal water loss value, epidermal total lipid value, etc. should be considered.
• oil-soluble substrates such as water-soluble substrates, emulsion bases, suspension bases, such as purified lanolin.
• These ointments include antioxidants (e.g. tocopherol, BHA, BHT, NDGA, etc.), preservatives (e.g. phenolic substances, chlorobutanol, benzyl alcohol, parabens, benzoic acid, etc.), moisturizers (e.g.
• Dissolution aids eg, ethanol, propylene glycol
• softening aids eg, liquid paraffin, glycerin, propylene glycol, surfactants, etc.
• a lotion When formulated into a lotion, it may be prepared in a lotion such as solution, suspension or emulsion type, and in the case of a lotion applied to the skin, for example, may be prepared to have a viscosity of 200 cps to 500 cps, and a soft feeling when applied. It is preferable to prepare a compound by combining a humectant such as glycerin and propylene glycol.
• a propellant or the like When formulated with a spray, a propellant or the like may be combined with the additives to disperse the dispersed dispersion or wet powder.
• absorption accelerators When formulated as a patch, absorption accelerators can be used to increase the absorption of the compound through the skin.
• compositions of the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.
• Formulations of the pharmaceutical compositions of the present invention include powders, granules, tablets, capsules, suspensions, emulsions, syrups, oral formulations such as aerosols, external preparations such as ointments, creams, suppositories, sterile injectable solutions, etc. It may be used in any form suitable for pharmaceutical formulations, including.
• the pharmaceutical composition according to the present invention can be administered to mammals such as rats, mice, livestock, humans by various routes such as parenteral, oral, and all modes of administration can be expected, for example, oral, It may be administered by rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection. At this time, as a parenteral route, transdermal administration is preferred, and topical application is most preferred.
• the topical administration includes transdermal delivery resulting in systemic effects.
• excipients e.g. lactose, starch, cellulose, lactose, polyethylene glycol, etc.
• lubricants e.g. magnesium stearate, stearic acid, glyceryl behenate, talc, etc.
• preservatives e.g. benzyl Alconium chloride, etc.
• composition of the present invention is administered in a pharmaceutically effective amount.
• pharmaceutically effective amount means an amount sufficient to treat or prevent a disease at a reasonable benefit / risk ratio applicable to medical treatment or prophylaxis, and an effective dose level means the type of disease and its severity; Activity of the drug; The age, body weight, health and sex of the patient; Sensitivity to the drug of the patient; The time of administration, route of administration, and rate of excretion of the specific extract used; Duration of treatment; It may be determined according to factors including drugs used in combination or coincidental with the specific extract used and factors well known in the medical arts.
• the oral dosage form may vary depending on the age, sex, and weight of the patient, but the amount of 0.1 to 100 mg / kg may be administered once to several times a day.
• the present invention relates to a method for whitening skin by applying the cosmetic composition or pharmaceutical composition of the present invention to the skin of a mammal, including a human.
• whitening refers to preventing or improving blackening of the skin caused by the deposition of melanin due to various causes such as aging, ultraviolet rays, contaminated environment, and the like.
• the platicodine-D of the present invention is excellent in inhibiting tyrosinase activity and inhibiting melanin production by at least about 10% even when compared to vitamin C (vitamin C) conventionally used as a raw material for cosmetics for the purpose of skin whitening. It was. Therefore, Platicodine-D, which is included as an active ingredient in the cosmetic composition and the pharmaceutical composition of the present invention, has an excellent skin whitening effect, and thus the skin may be effectively whitened by applying the composition to the skin.
• vitamin C vitamin C
• the cumulative skin irritation test against platicodine-D was found to be a natural substance that is harmless to humans. Therefore, the platicodine-D of the present invention has little toxicity and side effects, so it can be used safely even in long-term use, and in particular, it can be safely applied to cosmetic compositions and pharmaceutical compositions as described above.
• B16 melanoma cells were used to measure the inhibitory effect of melanin production by Platicodin-D (Sigma), and this was compared with the melanin production inhibitory effect of vitamin C, which is known to inhibit melanogenesis.
• This experiment was performed using murine melanoma (B-16 F10) cells in DMEM medium containing 10% fetal bovine serum (FBS) in 6-well plates at 1 ⁇ 10 per well. 5 After inoculation with dogs, 5% CO 2 And Cells were incubated at 37 ° C. until they were at least about 80% adhered to the bottom of the well. After incubation, remove the medium and replace Platicodin-D and vitamin C in a DMEM medium diluted to the appropriate concentration, 5% CO 2, Incubated at 37 ° C. for 3 days. The concentration range of Platicodin-D was determined to be 0.1 uM, 0.5 uM, 1 uM without cytotoxicity.
• the concentration range of vitamin C was 0.1 uM, 0.5 uM, 1 uM in the same manner as Platicodin-D.
• the medium was removed, and the collected cells were washed with PBS (phosphated buffer saline) and treated with trypsin to recover the cells.
• the recovered cells were counted using a hematocytometer, centrifuged at 5,000 to 10,000 rpm for 10 minutes, and then the supernatant was removed to obtain pellets.
• the cell pellet was dried at 60 ° C., and 100 ⁇ l of 1 M sodium hydroxide solution containing 10% DMSO was added to obtain intracellular melanin in a 60 ° C. thermostat. Using this solution, the absorbance at 490 nm was measured with a microplate reader to determine the amount of melanin per cell. The results are shown in Table 1 below.
• Rat pigment cells (B16 melanoma cells) were used to measure the inhibitory effect of melanin production by placodin-di and compared with the inhibitory effect of intracellular tyrosinase activity by vitamin C, which is known to inhibit melanin production.
• murine melanoma (B-16 F1) cells were inoculated in DMEM medium containing 10% FBS (fetal bovine serum) at 1 ⁇ 10 5 per well in a 6-well plate, followed by 5% CO 2 at 37 ° C. The cells were cultured until at least 80% of the cells adhered to the well bottom. After incubation, the medium was removed and Platicodin-D and Vitamin C were replaced with DMEM medium diluted to appropriate concentrations and incubated at 5% CO 2, 37 ° C. for 3 days. The concentration ranges of platicodine-di and vitamin C were 0.1 uM, 0.5 uM, and 1 uM as in Example 1.
• the medium was removed, and the collected cells were washed with PBS (phosphated buffer saline), which was treated with trypsin to recover the cells.
• the recovered cells were counted using a hematocytometer, centrifuged at 5,000 to 10,000 rpm for 10 minutes, and then the supernatant was removed to obtain pellets.
• the cell pellet was pulverized using lysis buffer, and the supernatant was collected by centrifugation at 12,000 rpm for 10 minutes. Using this solution, the absorbance was measured at 492 nm using a microplate reader to determine the cell number tyrosinase activity. The results are shown in Table 2 below.
• platycodine-di showed better intracellular tyrosinase inhibition than vitamin C.
• the aluminum foil was peeled off and a sample (platicodine-di and vitamin C) was applied in the following manner. Pigmentation appeared 2 or 3 days after the UV irradiation, and reached a peak after about 2 weeks, and each sample was applied therefrom.
• the effect was determined by measuring the degree of black and white of the skin using a color difference meter (Minolta CR2002 chromameter), the results are shown in Table 3 below.
• L * A * B * colorimeter is used to display color, and L * value was used as an index in this invention.
• L * value was calibrated with a standard whiteboard, and L * value was measured 5 times or more at one site, and pigmentation was equalized.
• the difference (L * ) between the skin color at the start of application and at the end of application was determined and the effect was judged by this value. Comparing the L * value for the sample application site and the control site and comparing the effect of the whitening material can be seen. The results are shown in Table 3 below.
• Platicodin-D showed a better whitening effect than vitamin C, and cumulative irritation was not observed during the test application of the test substance, and thus safety was also excellent.
• Skin external preparations containing Platicodin-di and vitamin C were prepared by the ingredient contents of Table 4 below.
• the control group is an external skin preparation that does not include a tyrosinase inhibitor
• test group 1 and test group 2 are external skin preparations including platicodine-D and vitamin C, respectively.
• Control Test group 1 Test group 2 Purified water 72 72 72 glycerin 8.0 8.0 8.0 Butylene glycol 4.0 4.0 4.0 Platicodin-D 0 1.0 0 Vitamin c 0 0 1.0 Caprylic Capri Triglyceride 8.0 8.0 8.0 Squalane 5.0 5.0 5.0 Cetearyl Glucoside 1.5 1.5 1.5 Sorbitan stearate 0.4 0.4 0.4 Cetearyl Alcohol 1.0 1.0 1.0 1.0 Trimethanolamine 0.1 0.1 0.1 Gross weight 100 100 100 100 100 100 100 100
• Platicodine-D stimulates the skin by performing a total of nine 24-hour cumulative blisters on the upper forearm every other day in 30 healthy adults using each skin preparation prepared in Example 4-1. It was measured whether or not giving.
• the patch method used the fin chamber (Finn chamber, Epitest Ltd, Finland). 15ul of each said skin external preparation was dripped at the chamber, and the patch was performed. The degree of response to the skin each time was scored using the following Experimental Formula 2, and the results are shown in Table 5 below.
• Average responsiveness [[response index x responsiveness / total number of subjects x highest score (4 points)] x 100] ⁇ Number of tests (9 times)
• the external skin preparations containing Platicodin-D did not show a distinct cumulative stimulation pattern as the external skin preparations containing the control or vitamin C and was determined to be a safe substance for human skin. .
• Platicodin-D of the present invention has a higher inhibitory effect on intracellular tyrosinase and a melanin production inhibitory effect than vitamin C, which is a main component of the existing whitening agent.
• vitamin C which is a main component of the existing whitening agent.

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• 2009
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