Classifications

• • 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
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
  • A61K8/0212—Face masks
• • 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
• • 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
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
• • 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
  • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
  • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
  • A61K8/9783—Angiosperms [Magnoliophyta]
  • A61K8/9789—Magnoliopsida [dicotyledons]
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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 cosmetic composition and more particularly, to a cosmetic composition for skin whitening comprising senkyunolide A as an active ingredient and its applications.
• UV-irradiated epidermal keratinocytes secrete melanin-inducing factors resulting in synthesis of melanin from activated dermal melanocytes and the secreted melanin on epidermis pigments the skin.
• tyrosinase converts tyrosine into dopaquinone and its oxidized derivative, dopachrome, is consecutively oxidized into 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA).
• DHI 5,6-dihydroxyindole
• DHICA 5,6-dihydroxyindole-2-carboxylic acid
• tyrosinase inhibitors are kojic acid, albutin, hydroquinone, vitamin C and extracts of various natural materials.
• the present inventors have been endeavored to alleviate the melanin-inducing stimuli such as UV irradiation and to inhibit the UV-derived physiological activity and synthesis of melanin-inducing factors.
• the present inventors gave a due investigation on candidate substances enabling to inhibit melanin synthesis induced by melanocyte-stimulating hormone (MSH).
• MSH melanocyte-stimulating hormone
• ⁇ -melanocyte stimulating hormone (CL MSH) expressed by UV irradiation or pregnancy binds to its receptor on melanocyte leading to increase of melanin via activation of melanocyte, tyrosinase and melanocyte dendrite. Consequently, it is highly probable to gain skin-whitening effect and alleviation of pigmentation by inhibiting a MSH. For that reason, the need of inhibitors for a MSH has been highly rising in the art.
• MSH melanocyte stimulating hormone
• a cosmetic composition for skin whitening comprising: (a) a senkyunolide A as an active ingredient; and (b) a cosmetically acceptable carrier.
• composition for inhibiting melanocyte-stimulating hormone comprising senkyunolide A as an active ingredient.
• Senkyunolide A (3-butyl-6,7-dihydrophthalide), a naturally occurring phthalide, is represented by the following formula I:
• the senkyunolide A used has been isolated from Cnidium officinale or Ligusticum chuanxiong , which are perennial herbs of Umbelliferae.
• Cnidium officinale comprises ligustilide, butylidenephthalide, sekyunolide A and sekyunonlide H (Kobayashi S. et al., Antiproliferative effects of the traditional Chinese medicine shimotsu-to, its component Cnidium rhizome and derived compounds on primary cultures of mouse aorta smooth muscle cells. Jpn J Pharmacol. 1992.
• Ligusticum chuanxiong comprises 3-butylphthaldie, 3-butylidenephthalide, 3-butylidene-4-hydroxyphthalide, neocnidilide, Z-ligustilide, E-ligustilide, senkyunolide A, senkyunolide F, senkyunolide H and senkyunolide I (Li H X. et al., Separation and identification of the phthalic anhydride derivatives of Liqusticum chuanxiong Hort by GC-MS, TLC, HPLC-DAD and HPLC-MS. 2002. J Chromatogr Sci. 40(3): 156-61).
• the senkyunolide A of the invention showed a novel MSH-inhibitory activity and more enhanced skin-whitening effect than conventional whitening agents showing inhibition of tyrosinase activity.
• the purified senkyunolide A according to the present invention is a potential candidate for skin-whitening agent since its IC 50 is much lower than extract of Cnidium officinale or Ligusticum chuanxiong.
• senkyunolide A of the present invention is isolated from the extract of Cnidium officinale or Ligusticum chuanxiong .
• the extract of Cnidium officinale or Ligusticum chuanxiong may be acquired using various extraction solvents, e.g. (a) water, (b) anhydrous or hydrous lower alcohol containing 1-4 carbon atoms (methanol, ethanol, propanol, butanol, etc.), (c) mixture of the lower alcohol and water, (d) acetone, (e) ethyl acetate, (f) chloroform, (g) 1,3-butyleneglycol, (h) butyl acetate.
• More preferable extraction solvent for this invention is the hydrous lower alcohol, and the most preferable solvent is ethanol.
• other conventional solvents may be employed for substantially similar isolating efficiency.
• Senkyunolide A according to the present invention can be isolated and purified from Cnidium officinale or Ligusticum chuanxiong using the known methods in the art.
• the isolation and purification may employ gas chromatography (GC), head space gas chromatography (HSGC), liquid chromatography (LC), high performance liquid chromatography (HPLC) and thin layer chromatography (TLC).
• GC gas chromatography
• HSGC head space gas chromatography
• LC liquid chromatography
• HPLC high performance liquid chromatography
• TLC thin layer chromatography
• the present invention may employ senkyunolide A prepared by not only isolating from Cnidium officinale or Ligusticum chuanxiong extract but also synthesizing chemically.
• the effective amount of senkyunolide A in cosmetic composition is 0.00001-20 wt %, and more preferably 0.00001-10 wt % based on the total weight of the cosmetic composition.
• the amount of senkyunolide A is lower than 0.00001 wt %, the aimed skin-whitening effect may be negligible; in the case of exceeding 20 wt %, some adverse effects such as skin irritation and instability in formulation is very likely to occur.
• the cosmetic compositions of the present invention may contain auxiliaries as well as carrier in addition to senkyunolide A.
• auxiliaries include preservatives, antioxidants, stabilizers, solubilizers, vitamins, colorants, odor improvers or mixtures of these ingredients.
• the cosmetic compositions of this invention may be formulated in a wide variety of form, for non-limited example, including a solution, a suspension, an emulsion, a paste, an ointment, a gel, a cream, a lotion, a powder, a soap, a surfactant-containing cleanser, an oil, a powder foundation, an emulsion foundation, a wax foundation and a spray.
• the cosmetic composition of the present invention can be provided in a form of skin softener (skin lotion), astringent lotion, nutrient emulsion (milk lotion), nutrient cream, message cream, essence, eye cream, cleansing cream, cleansing foam, cleansing water, facial pack, spray or powder.
• the cosmetically acceptable carrier contained in the present cosmetic composition may be varied depending on the type of the formulation.
• the formulation of ointment, pastes, creams or gels may comprise animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc, zinc oxide or mixtures of these ingredients.
• powder or spray it may comprise lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder and mixtures of these ingredients.
• Spray may additionally comprise the customary propellants, for example, chlorofluorohydrocarbons, propane/butane or dimethyl ether.
• the formulation of solution and emulsion may comprise solvent, solubilizer and emulsifier, for example water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils, in particular cottonseed oil, groundnut oil, maize germ oil, olive oil, castor oil and sesame seed oil, glycerol fatty esters, polyethylene glycol and fatty acid esters of sorbitan or mixtures of these ingredients.
• solvent solubilizer and emulsifier
• solubilizer and emulsifier for example water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils, in particular cottonseed oil, groundnut oil, maize germ oil, olive oil
• the formulation of suspension may comprise liquid diluents, for example water, ethanol or propylene glycol, suspending agents, for example ethoxylated isosteary alcohols, polyoxyethylene sorbitol esters and poly oxyethylene sorbitan esters, micocrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures of these ingredients.
• liquid diluents for example water, ethanol or propylene glycol
• suspending agents for example ethoxylated isosteary alcohols, polyoxyethylene sorbitol esters and poly oxyethylene sorbitan esters, micocrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures of these ingredients.
• the formulation of cleansing compositions with surfactant may comprise aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosucinnate monoester, isothinate, imidazolium derivatives, methyltaurate, sarcocinate, fatty acid amide ether sulfate, alkyl amido betain, aliphatic alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanoline derivatives, ethoxylated glycerol fatty acid ester or mixtures of these ingredients.
• R f 0.5 was pre-determined via prep-TLC with the control of senkyunolide A commercially available.
• senkyunolide A 3.1 g was finally purified through prep-LC, distillation under vacuum and removal of residual solvent using vacuum pump, consecutively:
• Melanocytes (mouse B-16 melanoma strain; ATCC CRL 6323) were purchased from ATCC (USA). The melanocytes were maintained in T-flask supplemented with DMEM containing 4.5 g/L glucose, 10% FBS (fetal bovine serum) and 1% penicillin-streptomycin in a humidified incubator supplied with 5% CO 2 at 3° C. After 24 h incubation, cells were detached by trypsinization and 5 ⁇ 10 4 cells were plated on each 100 mm plate supplemented with fresh medium.
• DMEM fetal bovine serum
• senkyunolide A according to the present invention was found to decrease melanin synthesis of melanocytes induced by MSH in a dose dependent manner and 50 ⁇ g/ml of senkyunolide A inhibited the melanin synthesis to the level below the amount of MSH-uninduced melanocytes (100%).
• senkyunolide A of the present invention was found to decrease the tyrosinase expression in melanocytes in a dose dependent manner and 50 ⁇ g/ml senkyunolide A caused the similar band intensity to tyrosinase of MSH-uninduced melanocytes.
• the formulations of the present invention can be provided in a form of skin softener (skin lotion), astringent lotion, nutrient emulsion (milk lotion), nutrient cream, message cream, essence, facial pack without limiting the applicable formulations therein.
• Formulation I Skin Lotion (Skin Softener)
• One example of skin lotion containing senkyunolide A according to the present invention is formulated as below: TABLE III Ingredients Amount (wt %) Senkyunolide A 1.0 Glycerine 5.0 1,3-butylglycol 3.0 PEG 150 1.0 Alantoine 0.1 DL-pantenol 0.3 EDTA-2Na 0.02 Benzophenon-9 0.04 Sodium hyaluronate 5.0 Ethanol 10.0 Octyldodeces-16 0.2 Polysorbate 20 0.2 Antiseptic, fragrant, colorant Small amount DW To be total Total 100
• astringent lotion containing senkyunolide A of the present invention is formulated as below Table IV: TABLE IV Ingredients Amount (wt %) Senkyunolide A 1.0 Glycerine 2.0 1,3-butylglycol 2.0 Alantoine 0.2 DL-pantenol 0.2 EDTA-2Na 0.02 Benzophenon-9 0.04 Sodium hyaluronate 3.0 Ethanol 15.0 Polysorbate 20 0.3 Witchhazel extract 2.0 Citric acid Small amount Antiseptic, fragrant, colorant Small amount DW To be total Total 100
• senkyunolide A of the present invention is formulated as below Table V: TABLE V Ingredients Amount (wt %) Senkyunolide A 1.5 Glyceryl stearate SE 1.5 Stearyl alcohol 1.5 Lanoline 1.5 Polysorbate 60 1.3 Sorbitan stearate 0.5 Hydrogenated vegetable oil 1.0 Mineral oil 5.0 Squalane 3.0 Trioctanoine 2.0 Dimethicon 0.8 Tocopherol acetate 0.5 Carboxyvinyl polymer 0.12 Glycerine 5.0 1,3-butylglycol 3.0 Sodium hyaluronate 5.0 Tri-ethanolamine 0.12 Antiseptic, fragrant, colorant Small amount DW To be total Total 100
• nutrient cream containing senkyunolide A of the present invention is formulated as below Table VI: TABLE VI Ingredients Amount (wt %) Senkyunolide A 5.0 Lypophilic glycerol monostearate 2.0 Cetearyl alcohol 2.2 Stearic acid 1.5 Wax 1.0 Polysorbate 60 1.5 Sorbitan stearate 0.6 Hydrogenated vegetable oil 1.0 Squalane 3.0 Mineral oil 5.0 Trioctanoine 5.0 Dimethicon 1.0 Sodium magnesium silicate 0.1 Glycerine 5.0 Betaine 3.0 Tri-ethanolamine 1.0 Sodium hyaluronate 4.0 Antiseptic, fragrant, colorant Small amount DW To be total Total 100
• TABEL VII Ingredients Amount (wt %) Senkyunolide A 1.0 Lypophilic glycerol monostearate 1.5 Stearyl alcohol 1.5 Stearic acid 1.0 Polysorbate 60 1.5 Sorbitan stearate 0.6 Isostearyl isostearate 5.0 Squalane 5.0 Mineral oil 35.0 Dimethicon 0.5 Hydroxyethyl cellulose 0.12 Glycerine 6.0 Tri-ethanolamine 0.7 Antiseptic, fragrant, colorant Small amount DW To be total Total 100
• One example of essence containing senkyunolide A of the present invention is formulated as below Table VIII: TABLE VIII Ingredients Amount (wt %) Senkyunolide A 1.5 Glycerine 10.0 Betaine 5.0 PEG 1500 2.0 Alantoine 0.1 DL-pantenol 0.3 EDTA-2Na 0.02 Benzophenon-9 0.04 Hydroxyethyl cellulose 0.1 Sodium hyaluronate 8.0 Carboxyvinyl polymer 0.2 Triethanolamine 0.18 Octyldodecanol 0.3 Octyldodeces-16 0.4 Ethanol 6.0 Antiseptic, fragrant, colorant Small amount DW To be total Total 100
• One example of facial pack containing senkyunolide A of the present invention is formulated as below Table IX: TABLE IX Ingredients Amount (wt %) Senkyunolide A 1.0 Polyvinyl alcohol 15.0 Cellulose gum 0.15 Glycerine 3.0 PEG 1500 2.0 Cyclodextrin 0.15 DL-pantenol 0.4 Alantoine 0.1 Monoammonium glycyrrhizinate 0.3 Nicotineamide 0.5 Ethanol 6.0 PEG 40 hydrogenated castor oil 0.3 Antiseptic, fragrant, colorant Small amount DW To be total Total 100
• the skin-whitening efficacy of the cosmetic compositions of the present invention was evaluated by practical use.
• the nutrient cream, containing 1.5% senkyunolide A, described in the Formulation IV was employed and senkyunolide A was substituted with the same amount of DW for control in this trial.
• the Formulation IV according to the present invention shows significantly enhanced whitening effect compared to its control formulation. Furthermore, there was no skin trouble in any testee.

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• 2002
  • 2002-10-29 KR KR10-2002-0066050A patent/KR100504408B1/ko active IP Right Grant
• 2003
  • 2003-01-15 FR FR0300394A patent/FR2846239B1/fr not_active Expired - Lifetime
  • 2003-01-28 CN CNB031034683A patent/CN1247182C/zh not_active Expired - Lifetime
  • 2003-01-29 US US10/353,010 patent/US20040081631A1/en not_active Abandoned
  • 2003-01-31 JP JP2003023372A patent/JP3889366B2/ja not_active Expired - Fee Related
• 2006
  • 2006-03-27 US US11/389,284 patent/US7846967B2/en active Active

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