DERMATOLOGICAL TOPICAL COMPOSITION

Abstract: Dermatological topical composition, comprising at least a mixture of uva-ursi and L-ascorbic acid and/or a derivative of L-ascorbic acid, or a mixture of an uva-ursi extract and L-ascorbic acid and/or a derivative of L-ascorbic acid further containing at least one compound selected from UV absorbers, allantoin or its derivatives, and pantethine-S-sulfonate or a salt thereof. The composition is useful as whitening and pigmentation reducing agent, preferably for the topical treatment of the human skin, preferably for effectively reducing skin problems caused by pigmentation such as liver spots, freckles and dark complexion.

Description: Dermatological topical composition The present invention refers to dermatological topical compositions which comprise a uva-ursi and L-ascorbic acid and/or a derivative of L-ascorbic acid, or an uva-ursi extract and L-ascorbic acid and/or a derivative of L- ascorbic acid and at least one compound selected from UV absorbers, allantoin or its derivatives, and pantethine-S- sulfonate or a salts thereof. In Japanese Tokkaihei 6-166609 there is disclosed that uva- ursi and its extracts can be active ingredients of whitening agents and pigmentation reducing agents. The contents of Tokkaihei 6-166609 is incorporated herein by reference. Skin problems due to pigmentation such as liver spots, freckles and dark complexion are reported to be due to excessive deposition of melanin in the skin. The invention disclosed in Tokkaihei 6-166609 shows that uva-ursi and its extracts are effective whitening agents and pigmentation reducing agents and are as effective as synthetic arbutin, which has been used as an whitening agent for many years. The purpose of the present invention is to use the whitening and pigmentation reducing effects of uva-ursi and its extracts for the preparation of dermatological topical compositions with effects superior to those of existing products of this category by combining uva-ursi and/or its extracts with ingredients which synergistically supplement or enhance their effects. The present invention refers to a dermatological topical composition characterized in that said composition comprises at least a mixture of uva-ursi and L-ascorbic acid and/or a derivative of L-ascorbic acid, or a mixture of an uva-ursi extract and L-ascorbic acid and/or a derivative of L- ascorbic acid further containing at least one compound selected from UV absorbers, allantoin or its derivatives, and pantethine-S-sulfonate or a salt thereof. The present invention further refers to a method of making a dermatological topical compositions according to the present invention said method comprising providing a composition comprising at least (i) a mixture of uva-ursi and L-ascorbic acid and/or a derivative of L-ascorbic acid, or (ii) a mixture of an uva-ursi extract and L-ascorbic acid and/or a derivative of L-ascorbic acid, and adding thereto at least one compound selected from UV absorbers, allantoin or its derivatives, and pantethine-S-sulfonate or a salt thereof. The present invention further refers to the use of said composition as a whitening and pigmentation reducing agent, especially for the topical treatment of the human skin to effectively reduce skin problems caused by pigmentation such as liver spots, freckles and dark complexion. However, dermatological topical agents according to this invention may be prepared by adding the components in any desired sequence and as mentioned, preferably by adding at least one of the following compounds to mixtures of uva-ursi and L-ascorbic acid and/or its derivatives, or mixtures of uva-ursi extract and L-ascorbic acid and/or its derivatives: UV absorbents, allantoin or its derivatives, and pantethine- S-sulfonate or at least one of its salts. Uva-ursi or the extract of uva-ursi is preferably made be drying and subsequently milling the leafs of arctostaphylos uva-ursi to any desired size. The obtained milled product is left in an aqueous extraction solvent for about 24 hours at room temperature, preferably under stirring. Such aqueous extraction solvent is preferably a mixture of an organic solvent with water, for example an alcohol or a polyol and water in a ratio of alcohol to water of 1:10 to 10:1, preferably 1:4 to 4:1. Preferred however within the scope of the present invention is an extraction solvent which is a mixture of acetone and water having a ratio of acetone to water from 1:10 to 10:1, preferably 1:5 to 5:1. The filtrate containing uva-ursi is carefully concentrated to dryness, preferably at a temperature below 50°C. The dry extract is dissolved in an aqueous solvent and submitted to an ultra- filtration. The resulting permeate is concentrated and filtrated and used according to the present invention. L-ascorbic acid, added to uva-ursi or its extract in the present invention, is generally known as vitamin C and has been shown to promotes cellular respiration, enzymatic activation and collagen formation and to reduce melanin by its potent reducing effects. Known derivatives of L-ascorbic acid include L-ascorbate monoalkylesters such as L-ascorbate monostearate, L-ascorbate monopalmitate and L-ascorbate monooleate; L-ascorbate monoester derivatives such as L- ascorbate monophosphate ester and L-ascorbate-2-sulfate; L- ascorbate diester derivatives such as L-ascorbate diphosphate esters, e.g. L-ascorbate distearate, L-ascorbate dipalmitate and L-ascorbate dioleate; trialkyl esters such as L-ascorbate tristearate, L-ascorbate tripalmitate and L- ascorbate trioleate; and L-ascorbate triester derivatives such as L-ascorbate triphosphate ester. One or two or more of these derivatives are selected under the present invention, i.e. may be added to the composition. The ratio of uva-ursi to vitamin C and/or the derivative thereof is preferably within the range of about 20:0.5 to 20:5, preferably about 20:0.5 to 20:2 and preferably about 20:1. Dermatological topical agents according to the present invention containing uva-ursi or its extract as the active ingredient to which L-ascorbic acid or its derivatives is added are further outlined in greater details below. Any known conventional UV absorber may be added to the dermatological composition of the present invention. Examples of UV-absorbers are Benzoate UV absorbers such as Paraaminobenzoate (PABA) , PABA monoglycerin ester, N,N- dipropoxy PABA ethyl ester, N,N-dietoxy PABA ethyl ester, N,N-dimethyl PABA ethyl ester, N,N-dimethyl PABA butylester, N,N-dimethyl PABA amylester, and N,N-dimetyl PABA octyl ester. Further examples are anthranilate UV absorbers, such as monomethyl-N-acetylanthranilate, homomenthyl-N- acetylanthranilate. Further examples are salicylate UV absorbents, such as amylsalicylate, methylsalicylate, homomenthylsalicylate, octylsalicylate, phenylsalicylate, benzylsalicylate, and p-isopropanolphenylsalicylate. Further examples are cinnamate UV absorbers such as octylcinnamate, ethyl-4-isopropylcinnamate, methyl-2,5- diisopropylcinnamate, ethyl-2, 4-diisopropylcinnamate, methyl-2, 4-diisopropylcinnamate, propyl-p-methoxycinnamate, isopropyl-p-methoxycinnamate, isoamyl-p-methoxycinnamate, isopropyl-p-methoxycinnamate, isoamyl-p-methoxycinnamate, octyl-p-methoxycinnamate (2-ethylhexyl-p-methoxycinnamate) , 2-ethoxyethyl-p-methoxycinnamate, cyclohexyl-p- methoxycinnamate, ethyl-alpha-cyano-beta-phenylcinnamate, 2- ethylhexyl-alpha-ciano-beta-phenylcinnamate, and glycerilmono-2-ethylhexanoil-diparamethoxycinnamate. Further examples are benzophenone UV absorbers such as 2,4- dihydroxybenzophenone, 2, 2 ' -dihydroxy-4-methoxybenzophenone, 2,2' -dihydroxy-4 , 4 ' -dimethoxybenzophenone, 2, 2 ' -4 , 4 ' - tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4 ' -methylbenzophenone, 2-hydroxy-4- methoxybenzophenone-5-sulfonate, 4-phenylbenzophenone, 2- ethylhexyl-4 ' -phenylbenzophenone-2-carboxylate, 2-hydroxy-4- n-octoxybenzophenone, and 4-hydroxy-3-carboxybenzophenone. Further useful UV absorbers are 3- (4 ' -methylbenzilidene) - d, 1-camphor, 3-benzilidene-d, 1-camphor, urocanic acid, ethylester urocanate, 2-phenyl-5-methylbenzoxazol, 2,2'- hydroxy-ethylbenzotriazol, 2- (2 ' -hydroxy-5 ' -t-actylphenyl) benzotriazole, 2- (2 ' -hydroxy-5 ' -methylphenyl) benzotriazole, dibenzaladine, dianisoilmethane, 4-methoxy-4 ' -t- butyldibenzoilmethane, 5- (3, 3-dimethyl-2-norbolnilidene) -3- pentane-2-on. There is no limitation to the content of UV absorbents in the dermatological topical composition according to the present invention whose active ingredient is uva-ursi to which L-ascorbic acid or its derivatives are added or uva- ursi extract to which L-ascorbic acid or its derivatives are added. Preferably, however, their content is 0.05%-10%, and preferably 0.5%-8%, calculated to the total weight of the dermatological topical preparation. UV absorbers do not prevent sunburn if their content is too low, and this offsets the whitening effects of uva-ursi or its extract. However, if contained in an excess amount, UV absorbers may affect the stability of the dermatological topical composition. WO 00/57840 — O , — PCT/EP00/02629 In addition to the essential ingredients mentioned above, other known and commonly used ingredients of cosmetic and pharmaceutical products may be added as necessary to the dermatological topical preparations according to the present invention. Such ingredients are for example oils, antioxidants, surfactants, moisturizing agents, flavors, water, alcohols, viscosity donors, antiseptics, colorants, powders, and drugs. The dermatological topical preparations according to the present invention may be made available in any dosage form, including solubilized preparations (such as toilet lotions) , emulsified preparations (milky liquid or creamy preparations), ointments, and dispersions. Dermatological topical compositions according to the present invention prepared by adding allantoin derivatives to uva- ursi or its extract containing L-ascorbic acid or its derivatives are outlined below. Allantoin derivatives used for this purpose include dihydroxyalluminum allantoinate and chlorohydroxyalluminum allantoinate. To reduce the present invention into practice, allantoin or 1 or 2 or more of its derivatives are selected as necessary. Their content should be 0.01%-5.0% (preferably 0.1%-3.0%) of the total weight of the dermatological topical preparations. The combination of allantoin or its derivatives and uva-ursi or its extracts containing L-ascorbic acid and/or its derivative (s) in dermatological topical preparations accoding to the present invention was found to result in synergistic effects on wounds and markedly promote their healing. Furthermore, said dermatological topical preparations show excellent wound healing effects even if base compounds are used that normally inhibit the wound healing process. This feature facilitates production because any base can be selected according to the objective of each dermatological topical preparation. Ingredients such as the following can be added as necessary to dermatological topical compositions according to the present invention prepared by adding allantoin or its derivatives to uva-ursi or its extract containing L-ascorbic acid or its derivatives: surfactants, oils, moisturizing agents, UV absorbers, antioxidants, antiseptics, flavors, water, alcohol, chelating agents, pH-adjusters, and/or viscosity donors. Dermatological topical preparations according to the present invention are not only useful in the form creams (such as nutrient creams, hand creams, body creams, and massage creams) , nutrient milky lotions, packs, and toilet waters but also as hair treatment compositions, in particular for scalp treatment. Dermatological topical preparations according to the present invention prepared by adding pantethine-S-sulfonate (PPS) or its salts to uva-ursi or its extract containing L-ascorbic acid or its derivatives are outlined below. PPS is a known compound whose general chemical formula is shown below as formula (I) . HOCH2C(CH 3 ) 2 CH(OH)CONHCH 2 CH 2 C0NHCH 2 CH 2 SSO 3 H (I) In nature, compound of formula (I) is found in carrots and is known as a factor that promotes the growth of Bifidobacterium bifidum. It is also known to exert whitening effects . PSS can be used in the form of the free acid or in its salt form. Although a wide range of organic and inorganic acid salts can be employed, alkali metal salts and alkali earth metal salts thereof are preferred. According to the present invention, PPS and/or its salts are used with uva-ursi at weight ratios of PPS and/or its salts to uva-ursi of 1:0.1 or higher, preferably at weight ratios of 1:0.1 to 1:10 and more preferably at 1:0.5 to 1:5. The ratio of less than 1:0.1 is undesirable because a sufficient stabilising effects cannot be obtained. Ingredients generally used for cosmetics, drugs and other products such as the following can be added as necessary to the dermatological topical compositions according to the present invention in addition to uva-ursi, PSS or its salts. Such products are aqueous ingredients, powdered ingredients, surfactants, moisturizing agents, viscosity donors, UV absorbers, colorants, drugs, and flavors. These ingredients of course must be added in quantities and quality standards that do not affect the effects of the composition according to the present invention. Dermatological topical preparations under the present invention may be produced in any dosage form, including those commonly used for topical preparations of this type such as ointments, creams, milky lotions and lotions. Example 1 100 parts of leafs of arctostaphylos uva-ursi was dried at 75 °C for 24 hours and milled to a fine powder. The obtained powder was mixed with 300 parts of a water/acetone mixture (80 parts of water, 20 parts of acetone) and left at room temperature under stirring for 24 hours. The mixture was then filtered and concentrated under vacuum at a temperature of 45°C to a third of its original volume. The concentrate was then treated in an ultra-centrifuge to separate from any fine components. The concentrate was then further concentrated to a volume of about 50 ml and left at a temperature of 5°C where upon a crystallised product of uvi-ursi was obtained. Both the crystallised product as well as the obtained concentrate were used to prepare the composition of the present invention.

Claims: Claims 1. Dermatological topical composition, characterized in that said composition comprises at least a mixture of uva-ursi and L-ascorbic acid and/or a derivative of L- ascorbic acid, or a mixture of an uva-ursi extract and L- ascorbic acid and/or a derivative of L-ascorbic acid further containing at least one compound selected from UV absorbers, allantoin or its derivatives, and pantethine-S-sulfonate or a salt thereof. 2. Composition according to claim 1, wherein uva-ursi or the extract of uva-ursi is obtained from arctostaphylos uva-ursi by extraction with an aqueous extraction solvent containing a mixture of an organic solvent and water, said organic solvent being an alcohol, a polyol or acetone, preferably acetone. 3. Composition according to claim 2, wherein the aqueous extraction solvent is a mixture of acetone and water having a ratio of acetone to water from 1:10 to 10:1, preferably 1:5 to 5:1. 4. Composition according to claim 2 wherein the uva- ursi has been obtained by crystallisation representing a crystallised substance. 5. Composition according to any one of the claims 1 to 4, wherein the ratio of uva-ursi to vitamin C and/or the derivative thereof is within the range of 20:0.5 to 20:5, preferably 20:0.5 to 20:2 and preferably about 20:1. 6. Composition according to any one of the claims 1 to 4, wherein the UV-absorber is benzoate UV absorber, an anthranilate UV absorbers, a salicylate UV absorber, a cinnamate UV absorbers or a benzophenone UV absorber. 7. Composition according to any one of the claims 1 to 6, wherein the concentration of the UV-absorber is 0.05%- 10%, and preferably 0.5%-8%, calculated to the total weight of the composition. 8. Composition according to any one of the claims 1 to 7, wherein said composition further contains oils, antioxidants, surfactants, moisturizing agents, flavors, water, alcohols, viscosity donors, antiseptics, colorants, powders, and drugs. 9. Composition according to any one of the claims 1 to 8, wherein said composition is a solubilized preparations (such as toilet lotions), emulsified preparations (milky liquid or creamy preparations) , ointments, or a dispersion. 10. Composition according to any one of the claims 1 to 9, wherein said composition contains allantoin or its derivatives in a concentration of 0.01%-5.0%, preferably 0.1%-3.0%, of the total weight of the dermatological topical preparations. 11. Composition according to any one of the claims 1 to 10, wherein said composition containing allantoin and/or its derivatives, further containing surfactants, oils, moisturizing agents, UV absorbers, antioxidants, antiseptics, flavors, water, alcohol, chelating agents, pH-adjusters, and/or viscosity donors. 12. Composition according to any one of the claims 1 to 11, in the form of creams (such as nutrient creams, hand creams, body creams, and massage creams) , nutrient milky lotions, packs, and toilet waters and hair treatment compositions. 13. Composition according to any one of the claims 1 to 12, containing PPS and/or its salts at weight ratios of PPS and/or its salts to uva-ursi of 1:0.1 or higher, preferably at weight ratios of 1:0.1 to 1:10 and more preferably at 1:0.5 to 1:5. 14. Method of making a composition according to any one of the claims 1 to 13, said method comprising providing a composition comprising at least (i) a mixture of uva-ursi and L-ascorbic acid and/or a derivative of L-ascorbic acid, or (ii) a mixture of an uva-ursi extract and L-ascorbic acid and/or a derivative of L-ascorbic acid, and adding thereto at least one compound selected from UV absorbers, allantoin or its derivatives, and pantethine-S-sulfonate or a salt thereof. 15. The use of a composition according to any one of the claims 1 to 14 as whitening and pigmentation reducing agent, preferably for the topical treatment of the human skin. 16. The use according to claim 15 to effectively reduce skin problems caused by pigmentation such as liver spots, freckles and dark complexion.

Inventors: NAKAYAMA HIROKI, NAKAYAMA, HIROKI
Applicants: NAKAYAMA HIROKI, PENTAPHARM AG, NAKAYAMA, HIROKI
Application year: 2000
Main classification: A61K7
IPC codes: A61K8, A61K31, A61K36, A61P17, A61Q5, A61Q17, A61Q19