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    • 专利摘要:
    Mixtures of amides of hydroxy fatty acids with retinol or retinyl esters synergistically inhibit keratinocyte differentiation. Mixtures of hydroxy fatty acid amides with retinol or retinyl esters have the same effect as treated with retinic acid.
    公开号:KR20000048696A
    申请号:KR1019990702651
    申请日:1997-09-18
    公开日:2000-07-25
    发明作者:스튜어트 패톤 그랜저；안토니 빈센트 로링스；이안 리차드 스코트
    申请人:알 브이 테이트 (로드니 비버스 테이트), 에이치 드로이. 씨. 지. 오닌크, 이. 에디, 산드라 웨드워즈 (에스 제이 에드워즈)；유니레버 엔.브이.；
    IPC主号:
    专利说明:

    Skin Care Compositions Containing an Amide and a Retinoid}
    [2] Retinol (vitamin A) is an endogenous compound that occurs naturally in the body and is essential for normal epithelial cell differentiation. Natural and synthetic vitamin A derivatives have been widely used in the treatment of various skin disorders and have been used as skin repairing or regenerating agents. Retinic acid is used for the treatment of various skin diseases such as acne, wrinkles, psoriasis, geriatric spots and discoloration (eg, Vahlquist, A. et al., J. Invest. Dermatol., Vol. 94, Holland D.B. and Cunliffe, W.J. (1990), pp. 496-498; Ellis, C.N. et al., "Pharmacology of Retinols in Skin", Vasel, Karger, Vol. 3, (1989), pp. 249-252; Lowe, N.J., et al., "Pharmacology of Retinols in Skin", Vol. 3, pp. 240-248; PCT Patent Application No. WO 93/19743.
    [3] It is contemplated to use esters of retinol or retinyl over retinic acid. Retinol is an endogenous compound. Esters of retinol are hydrolyzed in vivo to produce retinol. Retinol and retinyl esters are believed to be more stable than retinic acid. Unfortunately, retinol and retinyl esters are less effective than retinic acid in improving skin.
    [4] The present invention is based, in part, on the discovery that a mixture of retinol or retinyl esters with amides of hydroxy fatty acids synergistically inhibits keratinocyte differentiation. The effect of hydroxy fatty acid amides mixed with retinol or retinyl esters was similar to that of retinic acid. Thus, mixtures of hydroxy fatty acid amides with retinol or retinyl esters mimic retinic acid but are easier and safer to use than retinic acid.
    [5] U.S. Pat.No. 5,057,501 to Thornfeldt discloses a method for the treatment of multi-lingual and eczema diseases using sesquiterpene compounds and compositions containing from about 0.025% to about 35% monocarboxylic fatty acids, esters, or amides. It is starting. In addition, the composition may comprise a retinoid. Tonfeld teaches that any retinoid, i.e., isotretinoin, tretinoin, ethtretin (all in stereoisomeric form of retinic acid) and ethretinate (ester of trimethoxyphenyl retinic acid) have proven effective against polysulfuric diseases have. PCT Application WO / 9325177 [Proctor and Gamble] contains a specific type of cyclic carboxamide coolant and contains retinoids such as retinic acid and derivatives thereof (e.g. cis and trans). It may include, and discloses a composition for topical application to the skin. PCT Application WO / 9403156 [Rhone Poulenc] includes topical formulations containing linoleic acid or derivatives as active ingredients for the treatment and prevention of impure skin (eg, papules, pustules, or acne-prone skin). A composition is disclosed, which composition may contain from 0.025% to 0.1% by weight of tretinoin. European Patent Application No. 0 388 275 [Pierre Fabre Cosmetique) discloses compositions for treating seborrhea containing zinc salts which may be alkyl carboxamides and zinc retinoates.
    [6] US Pat. No. 5,216,148 to Klaus et al. Discloses the use of certain carboxamide complexes for the treatment and prevention of tumors, skin diseases and skin aging.
    [7] US Pat. No. 4,380,549 to Van Scott et al. And US Pat. No. 4,363,815 to Yu et al. Use hydroxy acids or their amides to treat acne, dry skin, flaky skin, scaly skin. Therapies are being disclosed. EP 0 582 458 discloses the use of N, N- (1,4C alkyl) lauamides. EP 0 559 304 discloses the use of amides containing hydrocarbyl chains having at least 25 carbon atoms as a skin softening agent. Beauquey et al. Disclose a skin wash and conditioning composition containing 1-4C alkanolamide of 8-16C fatty acid, among other components, in US Pat. No. 5,308,551. British Patent No. 1,126,289 [Hoffman-La Roche] includes vitamin A alcohols or vitamin A esters, emulsifiers, and monocarboxylic acids (eg N, N-diethyl-acetamide, N, N The preparation of stock vitamins containing a solvent selected from alcohols or dialkyl amides of -dimethyl acetamide or N, N-dimethyl formamide) is disclosed. Vitamin recipes have a very high content, eg a minimum concentration of 250,000 I.U. Vitamins that are vitamin A / ml. In addition, the amides described in British Patent No. 1,126,289 do not include or mention melinamide.
    [8] European Patent Application No. 0 742 005 filed earlier [Unilever; Priority Date 8 May 1995, publication date 13 November 1996 (published after priority date of this application), a mixture of fatty acid amides and retinol or retinyl esters is disclosed. However, European Patent Application 0 742 005 does not teach amides of hydroxy fatty acids.
    [9] The preceding document does not describe skin conditioning compositions based on synergistic mixtures of hydroxy fatty acid amides and retinol or retinyl esters. Neither of the above mentioned prior documents discusses the need for an effective substitute for retinic acid.
    [10] Summary of the Invention
    [11] The present invention provides a composition comprising (a) 0.001% to 10% of a retinoid selected from the group consisting of retinol and retinyl esters; (b) 0.0001% to 50% of an amide of the hydroxy fatty acid; And (c) an acceptable vehicle for cosmetic use.
    [12] The invention also provides a skin conditioning cosmetic method comprising topically applying the composition of the invention to the skin. The invention further provides a cosmetic method that mimics the effect of retinic acid on the skin, comprising topically applying the composition of the invention to the skin.
    [13] As used herein, the term "conditioning" refers to the treatment and prevention of one or more of dry skin, photodamaged skin, the occurrence of wrinkles, aged spots, aged skin, acne, psoriasis, atopic dermatitis. In addition, the compositions are useful for providing skin radiance and / or controlling sebum secretion, and / or increasing stratum corneum elasticity and generally improving skin quality. The composition can be used to improve skin exfoliation and cell division proliferation.
    [14] The presence of hydroxy fatty acid amides in the products of the present invention substantially improves the performance of retinol or retinyl esters, ie, hydroxy fatty acid amides substantially improve the function of retinol or retinyl esters to perform cell proliferation. Hydroxy fatty acid amides, when used alone, have little or no effect of improving skin improvement, while hydroxy fatty acid amides substantially increase skin improvement when used in combination with retinol or retinyl esters.
    [15] That is, the present invention is based, at least in part, on the discovery of synergistic interactions between retinol or retinyl esters and hydroxy fatty acid amides.
    [16] According to the present invention, the inclusion of an effective amount of hydroxy fatty acid amide in a composition containing retinol or retinyl ester substantially improves the performance of the composition. Alternatively, low concentrations of retinol or retinyl esters can be included in compositions containing hydroxy fatty acid amides to equal the performance of similar formulations without amides.
    [1] The present invention relates to skin protection compositions containing amides and retinol or retinyl esters, and to cosmetics comprising applying the compositions to the skin.
    [17] The composition of the present invention contains as a first essential component a compound selected from the group consisting of retinol, retinyl esters and mixtures thereof.
    [18] The term "retinol" includes all retinol isomers such as trans-retinol, 13-cis-retinol, 11-cis-retinol, 9-cis-retinol, 3,4-didehydro-retinol. Preferred isomers are all trans-retinol, 13-cis-retinol, 3,4-didehydro-retinol, 9-cis-retinol. All trans-retinol is most preferred since it is widely marketed.
    [19] Retinyl esters are esters of retinol. The term "retinol" is defined above. Retinyl esters suitable for use in the present invention are C 1 -C 30 esters, preferably C 2 -C 20 esters, and most preferably C 2 , C 3 , and C 16 esters of retinol, which are easier to use. This is because it can be obtained. Examples of retinyl esters are retinyl palmitate, retinyl formate, retinyl acetate, retinyl propionate, retinyl butyrate, retinyl valerate, retinyl isovalerate, retinyl hexanoate, retinyl heptano Retinyl octanoate, retinyl nonanoate, retinyl decanoate, retinyl undecaneate, retinyl laurate, retinyl tridecanoate, retinyl myristate, retinyl pentadecanoate, Retinyl heptadecanoate, retinyl stearate, retinyl isostearate, retinyl nonadecanoate, retinyl arachidonate, retinyl behenate, retinyl linoleate, retinyl oleate, retinyl lac Tate, retinyl glycolate, retinyl hydroxy caprylate, retinyl hydroxy laurate, retinyl tartarate, but these It is not limited.
    [20] Preferred esters for use in the present invention are selected from retinyl palmitate, retinyl acetate and retinyl propionate, since they are most readily available commercially and are therefore the cheapest. Retinyl linoleate is also preferred because of its efficacy.
    [21] Retinoids are used in the compositions of the present invention in amounts of 0.001% to 10%, preferably in amounts of 0.01% to 1%, most preferably in amounts of 0.01% to 0.5%.
    [22] The second essential ingredient of the composition of the present invention is the amide of hydroxy fatty acid. The structure of hydroxy fatty acid amide is as follows:
    [23]
    [24] Wherein R 1 , R 2 and R 4 are each independently selected from hydrogen and hydroxylable aliphatic saturated or unsaturated straight or branched chain hydrocarbon chains containing 1 to 20 carbon atoms;
    [25] R 3 is — (CH 2 ) n where n is an integer from 0 to 18.
    [26] Preferably, R 1 , R 2 and R 4 each independently contain 2 to 20, more preferably 2 to 15, and most preferably 3 to 13 carbon atoms.
    [27] The hydroxy acid amide is preferably an amide of α- or β-hydroxy acid, ie n is 0 or 1.
    [28] The most preferred hydroxy fatty acid amides included in the compositions of the present invention are lactamide-monoethanolamide, C 13 -β-hydroxy acid amide (2-hydroxy-C 13 -amide), N-hydroxyethyl-2- Hydroxy-C 16 amide, 12-hydroxy-N- (2-hydroxyethyl) octadecanamide, and monoethanolamide of castor oil.
    [29] Amides are included in the compositions of the present invention in an amount of 0.0001% to 50%, preferably 0.01% to 10%, most preferably 0.1% to 5%.
    [30] <Acceptable vehicles for cosmetics>
    [31] The compositions according to the invention are also for use in cosmetics which act as diluents, dispersants or carriers for retinol and / or retinyl esters and hydroxy fatty acid amides in order to facilitate the distribution of the composition when the composition is applied to the skin. It includes acceptable vehicles.
    [32] Vehicles other than or with water can include liquid or solid emollients, solvents, curbs, thickeners and powders. Particularly preferred non-aqueous carriers are polydimethyl siloxane and / or polydimethyl phenyl siloxane. The silicone of the present invention may have a viscosity in the range of 10 to 10,000,000 mm 2 / s (centistokes) at 25 ° C. Particular preference is given to mixtures of low and high viscosity silicones. These silicones are commercially available from General Electric Company under the trade names Vicasil, SE and SF, and from the Dow Corning Company under the trade names 200 and 500 series. The amount of silicone that can be used in the composition of the present invention is in the range of 5% to 95% by weight, preferably 25% to 90% by weight of the composition.
    [33] Acceptable vehicles for cosmetics generally comprise 5% to 99.9% by weight, preferably 25% to 80% by weight of the composition and can be balanced in the absence of other cosmetic aids. Preferably, the vehicle is at least 50% by weight of the vehicle, more preferably at least 80% by weight of water. Preferably, water constitutes at least 50% by weight of the composition of the present invention, most preferably 60 to 80% by weight of the composition.
    [34] Optional Skin Enhancers and Cosmetic Additives
    [35] Depending on the average hydrophilic-lipophilic balance (HLB) of the emulsifiers used predominantly, oils or oily substances may be present together with emulsifiers providing oil-in-water emulsions or oil-in-water emulsions.
    [36] The composition of the present invention preferably comprises a sun blocker. Sunscreen agents include materials commonly used to block UV rays. Exemplary compounds are salicylates, cinnamates and derivatives of PABA. For example, octyl methoxycinnamate and 2-hydroxy-4-methoxy benzophenone (also known as oxybenzone) can be used. Octyl methoxycinnamate and 2-hydroxy-4-methoxy benzophenone are commercially available under the trade names Parsol MCX and Benzophenone-3, respectively. The exact amount of sunscreen used in the emulsion can vary depending on the desired degree of protection from the sun's UV rays.
    [37] Another preferred optional ingredient is selected from essential fatty acids (EFAs), i.e. fatty acids essential for the plasma membrane production of all cells, where in keratinocytes, EFA deficiency overproliferates the cells. Replenishment of EFA corrects this. EFA also enhances lipid biosynthesis of the epidermis and provides lipids for barrier formation of the epidermis. Essential fatty acids are preferably linoleic acid, γ-linolenic acid, homo-γ-linolenic acid, columbinic acid, eicosane- (n-6,9,13) -trienoic acid, arachidonic acid, timnodonic acid, hexaenoic acid and their Selected from the mixture.
    [38] Still other preferred optional ingredients are azoles such as klimbazole, biponazole, clotrimazole, ketoconazole, miconazole, econazole, itraconazole, fluconazole, terconazole, butoconazole, sulfonazole , Lionazole and mixtures thereof. The azole may be included in the composition of the present invention in an amount of 0.001 to 50% by weight, preferably 0.001 to 10% by weight, most preferably 0.1 to 5% by weight.
    [39] Emollients are often included in the cosmetic compositions of the present invention. The amount of such emollients may range from 0.5% to 50% by weight, preferably from 5% to 30% by weight of the total composition. Emollients can be classified into esters, fatty acids and alcohols, polyols and hydrocarbons under the general chemical category.
    [40] The ester may be mono- or di-ester. Acceptable examples of fatty di-esters include dibutyl adipate, diethyl sebacate, diisopropyl dimerate and dioctyl succinate. Acceptable branched fatty esters include 2-ethyl-hexyl myristate, isopropyl stearate and isostearyl palmitate. Acceptable tribasic acid esters include triisopropyl trilinoleate and trilauryl citrate. Acceptable straight chain fatty esters include lauryl palmitate, myristyl lactate, oleyl uvate and stearyl oleate. Preferred esters include coco-caprylate / caprate (a blend of coco-caprylate and coco-caprate), propylene glycol myristyl ether acetate, diisopropyl adipate and cetyl octanoate.
    [41] Suitable fatty alcohols and acids include compounds having 10 to 20 carbon atoms. Especially preferred are compounds such as cetyl, myristyl, palmityl and stearyl alcohol and stearyl acid.
    [42] Among the polyols that can act as emollients are straight and branched chain alkyl multivalent compounds. For example, propylene glycol, sorbitol and glycerin are preferred. Polymer polyols such as polypropylene glycol and polyethylene glycol may also be useful. Butylene and propylene glycol are also particularly preferred as penetration enhancers.
    [43] Exemplary hydrocarbons that can act as emollients are those having a hydrocarbon chain of 12 to 30 carbon atoms. Specific examples thereof include mineral oil, yellow waselin, squalene and isoparaffin.
    [44] Another category of functional ingredients in the cosmetic compositions of the invention is thickeners. The thickener will generally be present in an amount from 0.1 to 20%, preferably 0.5 to 10% by weight of the composition. Exemplary thickeners are B.F. It is a crosslinked polyacrylate material available under the trade name Carbopol from the B.F. Goodrich Company. Gums such as xanthan, carrageenin, gelatin, indo rubber, pectin and acacia bean gum can be used. Under certain circumstances, thickening can be achieved by materials that also act as silicones or emollients. For example, silicone gums and esters having a viscosity above 10 centistokes, such as glycerol stearate, have dual functionality.
    [45] Powders may be incorporated into the cosmetic compositions of the present invention. These powders include chalk, talc, kaolin, starch, smectite clay, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, aluminum starch octenyl succinate and mixtures thereof Can be mentioned.
    [46] In addition, other auxiliary subcomponents may be included in the cosmetic composition. These components may include colorants, opacifiers and flavorings. The amount of these other adjuvant subcomponents may range from 0.001% up to 20% by weight of the composition.
    [47] <Use of composition>
    [48] The composition according to the invention is intended primarily as a product for topical application to human skin, in particular as a skin conditioning agent and a skin softening agent, as a medicament for preventing or reducing the occurrence of wrinkled or aged skin.
    [49] In use, a small amount of the composition, such as 1 to 100 ml, is applied to an exposed area of the skin from a suitable container or applicator, and then spread over the skin using hands or fingers or a suitable device, if necessary Or rub from the skin.
    [50] <Product form and packing>
    [51] Topical skin treatment compositions of the invention may be suitably formulated into lotions, creams or gels. The composition may be packaged in a suitable container to suit the intended use of the consumer and its viscosity. For example, the lotion or cream may be packaged in a bottle or roll-ball applicator, or an injector driven aerosol device or a container equipped with a pump suitable for finger manipulation. If the composition is a cream, it may be stored in a jar or compression container, such as a tube or lid, which simply does not deform. The composition may also be included in a capsule as described in US Pat. No. 5,063,057.
    [52] Accordingly, the present invention provides a hermetically sealed container containing a composition acceptable for cosmetics as defined herein.
    [53] The following specific examples further illustrate the invention. Retinoids were obtained from Sigma.
    [54] <Materials and Methods>
    [55] Cell culture:
    [56] Dulbecco's Modified Eagle (DME) Hams F12 (1: 1) medium / 10 in the presence of 3T3 mouse fibroblasts examined to make a keratinocyte colony that divides keratinocytes from an isolated human by trypsin treatment from neonatal foreskin. Growth in% fetal bovine serum. Cells were grown under these conditions until their second passage and frozen for later use. After thawing frozen second passaged keratinocytes, they were plated onto the medium described above, grown for 5 days, and then they were 0.15 mM Ca containing Radish, Clonetics Corporation, San Diego, CA. Serum MCDB 153-based medium keratinocyte proliferation medium (KGM) or Gibco (GIBCO) product keratinocyte serum free medium (KSFM) containing 0.09 mM Ca. On day 7, when the cells were 80-90% confluent, they were trypsinized and plated in serum-free medium for various experiments.
    [57] <Transglutaminase Assay>
    [58] Transglutaminase Assay and Keratinocyte Differentiation
    [59] During the process of terminal differentiation in the epidermis, a 15 nm thick protein layer known as keratinized envelope (CE) formed on the inner surface of the cell periphery. CE consists of many unique proteins crosslinked together by the formation of N ε- (γ-glutamyl) lysine isodipeptide bonds catalyzed by the action of two or more different transglutaminase expressed in the epidermis. Transglutaminase I (TGase I) is abundantly expressed in the differentiated layers of the epidermis, especially in the granular layer, but not in the undifferentiated basal epidermis. Thus, TGase I is a useful marker of epidermal keratinocyte differentiation, meaning that the higher TGase I amount is more differentiated. Differentiation status of keratinocytes cultured in the following examples was evaluated using an ELISA based TGase I assay using TGase I antibodies.
    [60] For Example 1 the following method was used:
    [61] Keratinocytes (cultivated as described above) were plated in 96 well plates at a density of 3,000 cells per well in 200 μl medium. After incubation for 4 days, the medium was changed to a medium containing the test compound (6 replicates per test). The cells were incubated for an additional 72 hours before the media was aspirated and the plates stored at -70 ° C. The plates were removed from the freezer and the cells washed with PBS. 100 μl of sterile water was added, frozen at −70 ° C. and thawed to freeze crushed cells. Cells were incubated with PBS / 3% BSA (wash buffer, bovine serum albumin) at room temperature (R / T) for 1 hour and then rinsed with fresh aliquots of wash buffer. Cells were diluted at 1: 2,000 in wash buffer with 50 μl of primary antibody monoclonal anti-human transglutase mouse antibody (IgG) obtained from Biomedical Industries for 1 hour at 37 ° C. After incubation, rinse twice with wash buffer. Cells were then 1 at 37 ° C. with 50 μl of secondary antibody (Fab fragment, peroxidase conjugated anti-mouse antibody (IgG), obtained from Amersham) diluted 1: 4,000 in wash buffer. Incubate for hours and then rinse twice with wash buffer. Cells are incubated at room temperature and in the dark (under aluminum foil) for 5 minutes with 4 mg of o-phenylene diamine in 10 ml of 0.1 M citrate buffer (pH 5) and 3.3 μl of 30% H 2 O 2. I was. The reaction was stopped by the addition of 50 μl 4 NH 2 SO 4 . The absorbance of the sample was read at 492 nm in a plate reader. Of the six replicates, four were treated with both antibodies and two were treated only with the secondary antibody (ie to obtain background binding of the enzyme conjugated antibody). The amount of TGase I was determined by subtracting the background from the readings from each treatment and measuring the mean ± sd for replicates exposed to both antibodies.
    [62] For Example 2, the following method was used:
    [63] Keratinocytes (cultivated as described above) were plated in 96 well plates at a density of 3,000 cells per well in 200 μl of cell culture medium. After incubation for 4 days, the medium was changed to a medium containing the test compound (6 replicates per test). The cells were incubated for an additional 72 hours before the media was aspirated and the plates stored at -70 ° C. After removing the plate from the freezer, the cells were further frozen by freezing and thawing and then washed three times with PBS. Cells were incubated with TBS / 5% BSA buffer at room temperature (R / T) for 1 hour. Monoclonal anti-human transglutaminase (IgG) mouse antibody (primary antibody) obtained from Biomedical Technologies Inc., then cells diluted 1: 2,000 in TBS / 1% BSA buffer. ) Was incubated with 100 μl for 2 hours at 37 ° C. and then rinsed six times with wash buffer (TBS / 1% BSA / 0.05% Tween-20). Cells were then incubated at 37 ° C. for 2 hours with 100 μl of Fab fragment, peroxidase conjugated anti-mouse IgG antibody (secondary antibody), obtained from Amersham, diluted 1: 4,000 in wash buffer. Rinse three times with wash buffer and three times with PBS. Cells were incubated at room temperature and in the dark (under aluminum foil) for 5 minutes with 4 mg o-phenylene diamine and 10% H 2 O 2 in 10 ml of substrate solution (0.1 M citrate buffer, pH 5.0). I was. The reaction was stopped by the addition of 50 μl 4 NH 2 SO 4 . The absorbance of the sample was read at 492 nm in a plate reader. Of the six replicates, four were treated with both antibodies and two were treated only with the secondary antibody (ie to obtain background binding of the enzyme conjugated antibody). The amount of TGase I was determined by subtracting the background from the readings from each treatment and measuring the mean ± sd for replicates exposed to both antibodies.
    [64] DNA analysis
    [65] The amount of TGase I detected after treatment of cells can be influenced by the number of cells, i.e., the greater the number of cells, the greater the amount of TGase I detected. The amount of TGase I was normalized to the DNA content of the cells in the same well to remove the deviation due to the difference in cell numbers. DNA quantification is a particularly useful measure of cell number, including keratinocyte counts, since each cell has the same genome for all intents and purposes and therefore the same amount of DNA. Thus, the total DNA content of one well of cells is directly proportional to the number of cells in that well. TGase data was normalized to cell number using DNA quantification.
    [66] Keratinocytes were plated in 96 well plates at a density of 3,000 cells per well in 200 μl of medium. After incubation for 4 days, the medium was changed to a medium containing the test compound (6 replicates per test). Cells were incubated for an additional 72 hours before the medium was aspirated and the plates stored at -70 ° C for at least 1.5 hours. The plates were removed from the freezer and thawed for 30 minutes. 100 μl Hoechst dye (final concentration 1 μg / ml) per well was added and incubated for 15 minutes, covered and read in a fluorometer (360 nm excitation and 460 nm emission). The dye solution was removed and the wells were rinsed with PBS in the preparation for TGase assay.
    [67] Example 1
    [68] Retinic acid is more effective than retinol in changing keratinocyte differentiation.
    [69] The effect on the transglutaminase amount normalized to the DNA content of the cells after addition of retinic acid (RA) and retinol (ROH) was evaluated and the results are shown in Table 1 below.
    [70] process Mean TGase / DNA × 10 -4 ± sd (% control) p-value vs control p-value vs2.5 × 10 -7 M ROH p-value vs2.5 × 10 -8 M ROH p-value vs2.5 × 10 -9 M ROH Control 2.44 ± 0.24 (100%) - 0.001 0.001 0.001 2.5 × 10 -7 M RA 0.16 ± 0.11 (7%) 0.001 0.001 0.001 0.001 2.5 × 10 -7 M ROH 1.14 ± 0.22 (47%) 0.001 - 0.001 0.001 2.5 × 10 -8 M RA 1.34 ± 0.40 (55%) 0.001 0.2 0.001 0.001 2.5 × 10 -8 M ROH 1.89 ± 0.30 (77%) 0.001 0.001 - 0.001 2.5 × 10 -9 M RA 1.87 ± 0.49 (77%) 0.001 0.001 0.784 0.001 2.5 × 10 -9 M ROH 2.70 ± 0.59 (> 100%) 0.001 0.001 0.001 - n = 3
    [71] All concentrations of retinic acid tested, namely 2.5 x 10 -7 M, 2.5 x 10 -8 M and 2.5 x 10 -9 M, respectively, were compared with the corresponding 2.5 x 10 -7 M, 2.5 x 10 -8 M compared to the ethanol control. Keratinocyte differentiation was reduced to a significantly greater extent than M and 2.5 × 10 −9 M retinol treatment. The decrease in the amount of transglutaminase was dose dependent for both retinic acid and retinol. This is consistent with the greater inhibitory effect of retinic acid on epithelial differentiation than retinol.
    [72] Example 2
    [73] Amides and retinol of hydroxy fatty acids act synergistically to inhibit keratinocyte differentiation.
    [74] The effect on normalized TGase I concentration on the DNA content of the cells was tested by treatment with test compound for 72 hours. Amide was obtained from Quest International. C 13 β-hydroxy acid amide has the structure:
    [75]
    [76] Effects of Retinol and C 13 -β-hydroxy Acid Amides on Keratinocyte TGase / DNA process Mean TGase / DNA × 10 5 ± sd (% control) p value vs control p value vs2.5 × 10 -8 M ROH p-value vs2.5 × 10 -8 M RA p value vs10 -8 MC 13 -β-hydroxy acid amide Control 18.42 ± 3.88 (100%) - 0.001 0.001 0.875 2.5 × 10 -8 M RA 1.05 ± 1.05 (6%) 0.001 0.001 - 0.001 2.5 × 10 -8 M Retinol 14.62 ± 2.99 (79%) 0.001 - 0.001 0.001 10 -9 MC 13 -β-hydroxy acid amide 18.53 ± 4.58 (101%) 0.875 0.001 0.001 - 2.5 × 10 -8 M ROH + 10 -8 MC 13 -β-hydroxy acid amide 11.36 ± 2.43 (62%) 0.001 0.001 0.001 0.001 n = 3
    [77] 2.5 × 10 −8 M of retinic acid was very effective in inhibiting keratinocyte TGase I concentration (up to 6% of control concentration). 2.5 × 10 −8 M retinol was less effective than retinic acid (79%), and 10 −9 M C13 β-hydroxy acid amide alone had an inhibitory effect on the concentration of keratinocyte TGase I when used alone. Not shown. However, 2.5 × 10 −8 M retinol + 10 −8 M C13 β-hydroxy acid amide inhibited keratinocyte TGase I by 62% of control concentration. Thus, C13 β-hydroxy acid amide and retinol act synergistically to inhibit keratinocyte differentiation in the same way as for the effect of retinic acid.
    [78] The effect on normalized TGase I on the DNA content of the cells was tested by treatment with test compounds for 72 hours. "Lactamide MEA" is a lactamide monoethanolamide. This was obtained from Croda Chemicals. Lactamide MEA has the structure:
    [79]
    [80] Effect of Retinol and Lactamide MEA on Keratinocyte Differentiation process Mean TGase / DNA × 10 5 ± sd (% control) p value vs control p value vs2.5 × 10 -7 M ROH p-value vs2.5 × 10 -7 M RA p value vs10 -6 M lactamide - MEA Control 64.11 ± 3.19 (100%) - 0.110 0.002 0.001 2.5 × 10 -7 M RA 46.71 ± 7.83 (73%) 0.002 0.030 - 0.049 2.5 × 10 -7 M retinol 58.47 ± 6.25 (91%) 0.110 - 0.030 0.311 10 -6 M Lactamide-MEA 55.22 ± 2.43 (86%) 0.001 0.311 0.049 - 2.5 × 10 -7 M ROH + 10 -6 M lactamide-MEA 46.29 ± 6.79 (72%) 0.001 0.018 0.930 0.024 n = 3
    [81] 2.5 × 10 −7 M of retinic acid was effective at inhibiting keratinocyte TGase I concentration (up to 73% of control concentration). 2.5 × 10 −7 M retinol and 10 −6 M lactamide-DEA were less effective at inhibiting keratinocyte TGase I concentrations when used alone. However, 2.5 × 10 −7 M retinol + 10 −6 M lactamide-DEA inhibited keratinocyte TGase I up to 72% of control concentration. Thus, lactamide-MEA and retinol act synergistically to inhibit keratinocyte differentiation in the same way as for the effect of retinic acid.
    [82] Examples 1 and 2 show that retinic acid in a dose dependent manner inhibited keratinocyte differentiation. In Examples 1 and 2, retinic acid was used as a positive control and as a comparative compound for comparison with other compounds under analysis. Retinol was not effective in reducing keratinocyte differentiation.
    [83] However, the unexpected results of Examples 1 and 2 indicate that by mixing retinol or retinyl ester with a compound in which the effect of retinol on cultured keratinocytes shows little or no advantage in the amides of hydroxy fatty acids, ie by itself. It could be improved to a degree close to the effect of retinic acid. The above results indicate that amides of hydroxy fatty acids synergistically act with retinol or retinyl esters to reduce keratinocyte differentiation, mimicking the effects of retinic acid.
    [84] Examples 3-8 illustrate the topical compositions according to the present invention. The composition can be prepared in a conventional manner. These are suitable for cosmetic use. In particular, the composition is applied to wrinkled skin, rough skin, dry skin, brittle skin, aged skin and / or UV damaged skin to improve skin appearance and feel as well as to apply to healthy skin to It is suitable to prevent or delay degradation.
    [85] Example 3
    [86] This example shows a high internal phase oil-in-water emulsion comprising a composition of the present invention.
    [87] Wt% / weight Retinol 0.5 Fully Hydrogenated Coconut Oil 3.9 C 13 β-hydroxy fatty acid amide 5 Breeze 92 * 5 Benton 38 0.5 MgSO 4 7H 2 O 0.3 Butylated Hydroxy Toluene 0.01 Spices Enough water Up to 100 Brij 92 is a polyoxyethylene (2) oleyl ether.
    [88] Example 4
    [89] This example shows an oil-in-water cream comprising the composition of the present invention.
    [90] Wt% / weight Retinyl palmitate 0.15 Mineral oil 4 Lactamide MEA One Brij 56 * 4 Alpol 16RD * 4 Triethanolamine 0.75 Butane-1,3-diol 3 Xanthan gum 0.3 Spices Enough Butylated Hydroxy Toluene 0.01 water Up to 100 Brij 56 is cetyl alcohol POE (10) .Alfol 16RD is cetyl alcohol.
    [91] Example 5
    [92] This example shows an alcoholic lotion comprising the composition according to the invention.
    [93] Wt% / weight Retinyl palmitate 0.15 N-hydroxyethyl-2-hydroxy-C 13 amide 0.1 ethanol 40 Spices Enough Butylated Hydroxy Toluene 0.01 water Up to 100
    [94] Example 6
    [95] This example shows another alcoholic lotion comprising the composition of the present invention.
    [96] Wt% / weight Retinol 0.15 N-hydroxyethyl-2-hydroxy-C 16 amide 0.1 ethanol 40 Antioxidant 0.1 Spices Enough water Up to 100
    [97] Example 7
    [98] This example shows a sun protection cream comprising the composition of the present invention.
    [99] Wt% / weight Retinol 0.01 12-hydroxy-N- (2-hydroxyethyl) octadecanamide 0.1 Silicone oil 200cts 7.5 Glyceryl Monostearate 3 Cetosteryl alcohol 1.6 Polyoxyethylene- (20) -cetyl alcohol 1.4 Xanthan gum 0.5 Parsol 1789 1.5 Octyl methoxycinnamate [PARSOL MCX] 7 Spices Enough coloring agent Enough water Up to 100
    [100] Example 8
    [101] This example shows a non-aqueous skin care composition comprising the composition of the present invention.
    [102] Wt% / weight Retinic acid 0.15 Castor oil monoethanolamide One Silicone Sword SE-30 1 10 Silicone Fluid 345 2 20 Silicone Fluid 344 3 55.79 Squalene 10 Linoleic acid 0.01 cholesterol 0.03 2-hydroxy-n-octanoic acid 0.7 Vitamin E Linoleate 0.5 Vegetable oil 0.5 ethanol 2 Dimethyl silicone polymer having a molecular weight of at least 50,000 and a viscosity of at least 10,000 centistokes at 25 ° C., commercially available from GEC. 2 Dimethyl siloxane cyclic pentameric, from Dow Corning Corp .. Corning Corporation Products.
    权利要求:
    Claims (5)
    [1" claim-type="Currently amended] (a) 0.001% to 10% of a compound selected from the group consisting of retinol, retinyl esters, and mixtures thereof;
    (b) 0.0001% to 50% of an amide of the hydroxy fatty acid; And
    (c) A skin conditioning composition comprising an acceptable vehicle for a cosmetic.
    [2" claim-type="Currently amended] The composition of claim 1 wherein the retinyl ester is selected from the group consisting of retinyl palmitate, retinyl acetate, retinyl propionate, retinyl linoleate and mixtures thereof.
    [3" claim-type="Currently amended] The composition of claim 1 wherein component (a) is retinol.
    [4" claim-type="Currently amended] A skin conditioning cosmetology comprising topically applying the composition of claim 1 to the skin.
    [5" claim-type="Currently amended] A cosmetic method that mimics the effect of retinic acid on the skin, comprising applying the composition according to any one of claims 1 to 3 to the skin.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1996-09-27|Priority to US08/721,874
    1996-09-27|Priority to US08/721,874
    1996-09-27|Priority to US8/721,874
    1997-09-18|Application filed by 알 브이 테이트 (로드니 비버스 테이트), 에이치 드로이. 씨. 지. 오닌크, 이. 에디, 산드라 웨드워즈 (에스 제이 에드워즈), 유니레버 엔.브이.
    2000-07-25|Publication of KR20000048696A
    2002-01-15|Application granted
    2002-01-15|Publication of KR100315319B1
    优先权:
    申请号 | 申请日 | 专利标题
    US08/721,874|US5747051A|1996-09-27|1996-09-27|Skin care compositions containing an amide of a hydroxy fatty acid and a retinoid|
    US08/721,874|1996-09-27|
    US8/721,874|1996-09-27|
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