EP2771032A1 - Agent éclaircissant de la peau en photothérapie - Google Patents
Agent éclaircissant de la peau en photothérapieInfo
- Publication number
- EP2771032A1 EP2771032A1 EP12773216.2A EP12773216A EP2771032A1 EP 2771032 A1 EP2771032 A1 EP 2771032A1 EP 12773216 A EP12773216 A EP 12773216A EP 2771032 A1 EP2771032 A1 EP 2771032A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- skin
- light emitting
- emitting diode
- acid
- pled
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- 230000005855 radiation Effects 0.000 claims abstract description 71
- 239000002537 cosmetic Substances 0.000 claims abstract description 48
- 238000011282 treatment Methods 0.000 claims abstract description 40
- 150000001875 compounds Chemical class 0.000 claims description 79
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- 206010040829 Skin discolouration Diseases 0.000 claims description 50
- 238000000034 method Methods 0.000 claims description 29
- 239000002253 acid Substances 0.000 claims description 22
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- 206010023126 Jaundice Diseases 0.000 claims description 19
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- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 claims description 16
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- 206010023138 Jaundice neonatal Diseases 0.000 claims description 14
- 206010000496 acne Diseases 0.000 claims description 14
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- 208000002874 Acne Vulgaris Diseases 0.000 claims description 11
- 208000035484 Cellulite Diseases 0.000 claims description 10
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 10
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- PBSRSWFGYPZDAU-FFIPNUABSA-H trimagnesium;[(2r)-2-[(1s)-1,2-dihydroxyethyl]-3-oxido-5-oxo-2h-furan-4-yl] phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].OC[C@H](O)[C@H]1OC(=O)C(OP([O-])([O-])=O)=C1[O-].OC[C@H](O)[C@H]1OC(=O)C(OP([O-])([O-])=O)=C1[O-] PBSRSWFGYPZDAU-FFIPNUABSA-H 0.000 description 1
- UYPYRKYUKCHHIB-UHFFFAOYSA-N trimethylamine N-oxide Chemical compound C[N+](C)(C)[O-] UYPYRKYUKCHHIB-UHFFFAOYSA-N 0.000 description 1
- UEVAMYPIMMOEFW-UHFFFAOYSA-N trolamine salicylate Chemical compound OCCN(CCO)CCO.OC(=O)C1=CC=CC=C1O UEVAMYPIMMOEFW-UHFFFAOYSA-N 0.000 description 1
- 108010014402 tyrosinase-related protein-1 Proteins 0.000 description 1
- 229940035936 ubiquinone Drugs 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 229960003895 verteporfin Drugs 0.000 description 1
- 235000019245 violaxanthin Nutrition 0.000 description 1
- SZCBXWMUOPQSOX-PSXNNQPNSA-N violaxanthin Chemical compound C(\[C@@]12[C@](O1)(C)C[C@H](O)CC2(C)C)=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(\C)/C=C/C=C(\C)/C=C/[C@]1(C(C[C@@H](O)C2)(C)C)[C@]2(C)O1 SZCBXWMUOPQSOX-PSXNNQPNSA-N 0.000 description 1
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- 150000003700 vitamin C derivatives Chemical class 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 235000001892 vitamin D2 Nutrition 0.000 description 1
- 239000011653 vitamin D2 Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
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Classifications
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Definitions
- the present invention relates, inter alia. the use of melanin synthesis inhibitors for the treatment of skin diseases, wherein the skin is additionally exposed to the radiation from an artificial radiation source. Furthermore, the present invention relates to cosmetic treatments, as well as cosmetic and pharmaceutical preparations
- Phototherapy also called light therapy
- the fields of application here are very broad and include, for example, wound healing, the treatment of injuries, pain, the alleviation of side effects of chemotherapy and radiotherapy.
- LEDs light emitting diodes
- PDT photodynamic therapy
- GB 2360461 discloses a flexible fabric used for PDT. Here, however, classic light sources are used, whereby the light is transmitted through optical fibers. The light sources are not suitable for non-stationary use. They are only suitable for use in medical facilities.
- WO 93/21842 discloses a transportable device containing LEDs as a light source for phototherapy. However, this device is intended for outpatient therapy and is not suitable for mobile and / or private use.
- Rochester et al. GB 24082092 discloses a flexible, medical light source containing LEDs and used for diagnostic purposes to check blood levels.
- Vogle Klaus and Kallert Heiko disclose in EP 018180773 a device for irradiation of the skin.
- the light source used is OLEDs (organic light-emitting diodes).
- the device can be installed in garments or patches.
- OLEDs have several advantages over conventional light sources. Thus, OLEDs are not spotlights, but surface radiators. Furthermore, due to their structure, OLEDs allow the production of a very thin light source for use in phototherapy.
- OLEDs in phototherapy, such as, the use of OLEDs to treat psoriasis, acne,
- jaundice Skinfold aging, inflammation, wound healing or jaundice (jaundice), for example, the treatment of neonatal jaundice
- OLEDs and other radiation sources with similar properties can be incorporated, for example, in plasters, bandages, garments, headgear, sleeping bags or blankets, so that phototherapy can even be carried out in parallel with private or professional activities and without significant restrictions ,
- OLEDs also have positive psychological / emotional effects in the phototherapeutic treatment of neonatal jaundice in addition to the beneficial technical effects.
- Newborn jaundice nonatal jaundice or neonatal hyperbilirubinemia, lat. Icterus neonatorum
- Jaundice is caused by increased incorporation of bilirubin, a breakdown product of the red blood pigment hemoglobin, into the skin.
- storage reaches its maximum on the fifth day of life and then gradually decreases. This is a natural process and mostly harmless.
- the neonatal jaundice is not a medical one
- liver of neonates especially the liver of preterm infants
- a special enzyme is not or not produced in sufficient quantities.
- This enzyme is the so-called glucuronyltransferase, which participates in the conversion of fat-soluble bilirubin into a water-soluble product.
- a deficiency in the enzyme means that the fat-soluble bilirubin can not be eliminated via the bile or kidney and subsequently accumulates in the body.
- a treatment by irradiation with blue light of wavelength 460 nm must be initiated in time to prevent the kernicterus.
- the fat-soluble bilirubin is converted into a water-soluble product, which can be excreted via the bile and the kidneys.
- infants are typically irradiated under classical blue-light lamps with light of a wavelength of 460 nm.
- the neonates are often irradiated within an infant incubator, but in any case without close physical contact with the parents. Irradiation usually takes place in several units per day over a period of 2 to 14 days. In order to avoid damage to the retina, the eyes are connected here. In practice, therefore, the therapy repeatedly leads to an emotional stress situation for the child and the parents.
- the use of OLEDs and similar sources of radiation in phototherapy can overcome at least some of the disadvantages of classical treatment of infants. So can the new light sources, for example, be used in blankets or sleeping bags, so that during the irradiation at least the direct physical contact between child and parent can be made.
- the retina of the eye can be damaged by the high-energy light rays.
- the high-energy light rays There are also increased
- the advantage can also lie in a combination of both effects. It is therefore conceivable that one develops a phototherapy, in which the irradiation times are shortened, the effectiveness increased and also side effects can be reduced.
- the present invention has for its object to overcome the disadvantages indicated in the prior art and to develop new, effective ways.
- the present invention provides skin-lightening compounds for the therapeutic and / or cosmetic treatment of the skin with the simultaneous use of phototherapy, wherein an artificial radiation source is preferably used for phototherapy.
- skin-lightening compound is well known to the person skilled in the art and it is easily possible for him to resort to a multiplicity of equally active alternative skin-lightening compounds of the prior art without being inventive in the process that have a skin-lightening property.
- the skin lightening compounds have in common that they reduce the concentration of melanin in the skin.
- Melanins are reddish, brown or black pigments, which are formed by the enzymatic oxidation of tyrosine and which cause the coloring of the skin, hair or eyes in humans. They continue to occur, for example, in other vertebrates, microorganisms and plants. Melanin is formed in vertebrates in the melanocytes of the skin and in the retina of the eye. The formation of melanins in the skin leads to a natural sunscreen.
- the biological or biochemical mechanisms underlying the skin-lightening action of the compounds can sometimes be very different.
- Briganti et al. disclose three basic, important concepts for
- skin-lightening compounds are typically grouped into different categories, namely those that precede melanin synthesis (eg, regulation of tyrosinase transcription by C 2 -ceramide or tretinoin, regulation of tyrosinase glycosylation by calcium D-panthenol-S-sulphonate), those during melanin synthesis (eg: inhibition of tyrosinase by hydroquinone, kojic acid, 4-hydroxyanisole, methyl gentisate, 4-S-cystaminylphenol and derivatives thereof, ellagic acid, arbutin, resveratrol, aloesin, oxyresveratrol and azelaic acid; inhibition of peroxidase by methimazole phenols / - Catechols; product reduction and radical scavengers for reactive oxygen species (ROS) by ascorbic acid, alpha-tocopherol, ascorbyl palmitate, D and L alpha-
- Serine protease inhibitors niacinamides, lectins and neoglycoproteins, soybean / milk extract; Increasing the turnover of the skin by lactic acid, retinoic acid, glycolic acid, linoisic acid, liquiritin) cause a reduction of the melanin concentration in the skin.
- pantothenic acid and derivatives or salts thereof sodium or calcium pantothenate, pantetheins, pantethine ((2R) -2,4-dihydroxy-3,3) dimethyl-N- [2- (2-sulfanylethylcarbamoyl) ethyl] butanamides), phosphopantetheine, etc.
- hydroquinone or derivatives thereof hydroquinone glucosides such as arbutin, etc.
- glucosamines or derivatives thereof glucosamine esters such as acetylglucosamine, glucosamine ethers such as Glucosamine methyl ether, etc.
- kojic acid monoalkyl esters such as kojic acid monobutyrate, kojic acid monocaprylate and kojic acid monostearate, kojic acid monopalmitate or a di-fatty acid ester of kojic acid selected from kojic acid dipalmitate, kojic acid dibutyrate, kojic dioleate and kojic acid distearate or kojic acid monocinnamoate or kojic acid mono benzoate, rucinol, ellagic acid and derivatives or salts thereof (ellagic acid ethers such as ellagic acid tetramethyl ether, acyl derivatives of ellagic acid such as ellagic acid tetraacetate and ellagic acid tetrabenzoate etc.), niacinamides,
- 5-acylglutathiones such as S-lactoylglutathione; N, S-diacylglutathione diesters such as N, S-dioctanoylglutathione distearyl and N, S-dipalmitoylglutathione dicetyl; etc.
- resorcinol or derivatives thereof resorcinol, alkylated resorcinol such as 4-n-butylresorcinol, 4-isoamylresorcinol, 4-cyclohexylresorcinol and 5-methylresorcinol; halogenated resorcinol such as 4-chloro-resorcinol and 4-bromo-resorcinol.
- Skin-lightening compounds in the context of the present invention are not understood to mean compounds which are typically used as sunscreen filters and / or UV filters.
- Paeonia actiflora sweetwood (Glycyrrhiza glabra), Chinese sweetwood (Glycyrrhiza uralensis), Mitracarpus scaber extract, bearberry
- Mulberry (Morus alba), Paper mulberry (Broussonetia papyrifera), Suriname (Eugenina uniflora), Emblica (Emblica officinalis), Tree (Sophora flavescens), Okamura (Dictyopteris prolifera), Alga (eg Dictyota linearis, Sargassum fusiforme, Lomentaria catenata, Rhodymenia palmata , Sargassum ringgoldianum, coreanum, Sargassum confusum, Sargassum yezoense, Sphaerotrichia divaricata), dandruff heath
- Walnut tree (Sapindus mukurossi), vetch (Astragalus sinicus) Eucalyptus (Eucalyptus officinalis), Ginkgo (Ginkgo biloba), Wolfberry (Lycium chinense), Micromelum (Micromelum pubescens), Melothria (Melothria indica), Mangifera indica, Firethorn (Pyracantha fortuneana).
- R 2 to R 6 and R 9 to R 13 are each independently selected from H, OH, straight-chain or branched C to C 2 o-alkoxy groups, wherein the alkyl chains may each be interrupted by oxygen or nitrogen,
- Oxygen can be interrupted,
- R 2 to R 6 and R 9 to R 13 are each independently a carboxylic acid, phosphoric acid, sulfonic acid, sulfuric or sulfone function, which may optionally be esterified or alkylated with straight-chain or branched C 2 -to-alkyl groups or straight-chain or branched C 3 - to C 20 -alkenyl groups,
- skin means all batches of the animal and human body which produce melanin for protection against radiation
- skin within the meaning of the present invention is understood as meaning both animal and human skin, preferably human skin.
- the use according to the invention of skin-lightening compounds in phototherapy can be used for any pharmaceutical and / or dermatological and / or cosmetic therapy or application.
- the effect of the radiation used can be increased and / or the side effects of harmful radiation can be reduced.
- Typical applications include but are not limited to psoriasis, atopic dermatitis, skin eczema, inflammation of the skin, acne, reduction and / or prevention of skin wrinkling, skin aging, pigmentation disorders (eg freckles, age spots), redness of the skin, comedones, and cellulite, stimulation of hair growth and the treatment of jaundice, especially in neonates.
- This tanning effect can be determined by means of a classification established under dermatologists be categorized. It is the so-called Fitzpatrick scale, according to which the skin is classified into different types I to VI.
- the present invention relates to skin lightening compounds for the therapeutic and / or cosmetic treatment of skin type III to VI, most preferably type IV to VI skin, and most preferably skin type V and VI, with simultaneous use of phototherapy , wherein for phototherapy preferably an artificial radiation source is used.
- the tanning effect can be further reduced by natural irradiation and / or by the phototherapy itself, as well as by the additional use of sunscreen filters, which will be explained in more detail below.
- a preferred object of the present invention relates to skin-lightening compounds for the therapeutic and / or cosmetic treatment of the skin with simultaneous use of phototherapy by means of an artificial radiation source, where icterus is to be treated, preferably neonatal jaundice.
- negroids and Asian newborns are understood as meaning children having a skin type III to VI, preferably a skin type IV to VI and very particularly preferably a skin type V and VI.
- one or more sun protection factors may be used in addition to the use of skin-lightening compounds.
- Another preferred subject of the present invention relates to compound according to claim, characterized in that the compound in the context of a cosmetic treatment for the elimination and / or reduction and / or prevention of skin aging, comedones, acne, formation of Hautfaiten and cellulite, pigmentary disorders (eg Freckles and age spots), and / or to stimulate hair growth, preferably for disposal and / or
- the artificial radiation source which can be used according to the invention is basically any radiation source used in phototherapy. So these can be classic lamps (eg UV or IR lamps), lasers or light emitting diodes. Particularly advantageous for the purposes of the present invention are radiation sources with very small dimensions. These include light emitting diodes (LED - light emitting diode); organic light-emitting diodes (OLED), polymeric light-emitting diodes (PLED) and organic light-emitting electrochemical cells (OLEC, LEC or also LEEC), preferably OLEDs, PLEDs and OLECs and very preferably OLEDs and PLEDs.
- LED - light emitting diode organic light-emitting diodes
- PLED polymeric light-emitting diodes
- OEC organic light-emitting electrochemical cells
- organic electroluminescent devices eg OLEDs, PLEDs, OLECs
- Semiconductors are used as functional materials, is well known to those skilled in the art and is described for example in US 4539507, US 5151629, EP 0676461 and WO 98/27136.
- OLEDs and PLEDs have a typical layer structure, wherein the number of layers in an OLED containing small organic molecules is usually less than the number of layers in a PLED.
- the organic functional materials used in an OLED or PLED can be any materials that one skilled in the art would consider.
- OLEDs / PLEDs include, for example, organic semiconductors, organic metal complexes, hole blocking materials (HBM), hole transport materials (HTM), hole injection materials (HIM), electron blocking materials (EBM), electron transport materials (ETM), electron injection materials (EIM), exciton blocking materials (ExBM ), Host materials, matrix materials, emitters, fluorescent emitters, phosphorescent emitters and dyes.
- PLEDs and / or OLEDs contain electrodes (anode, cathode). Furthermore, OLEDs and PLEDs may further contain materials, such as e.g. Buffer materials and encapsulating materials. Typical structures of OLEDs and PLEDs as well as common materials for electroluminescent devices are disclosed, for example, in WO 2004/058911 and in WO 2008/011953.
- OLECs organic light-emitting electrochemical cells, also called LEC or LEEC
- LEC organic light-emitting electrochemical cells
- ionic transition metal complexes ionic transition metal complexes
- ionic liquids ionic liquids
- the OLED / PLED / OLEC light sources have a planar or a more or less planar layer structure.
- the light sources can also be in fiber form.
- Organic light emitting fibers were, for example, in US 6538375 B1,
- the emitted wavelength can be adjusted by the skilled person without difficulty by the use of different emitters.
- the radiation sources thus allow a homogeneous irradiation of the skin.
- HIL hole injection layer
- HTL hole transport layer
- Electron blocking layer (EBL)
- EML emission layer
- ETL electron transport layer
- HBL Hole blocking layer
- EIL electron injection layer
- OLEDs may contain, in addition to said layers, others such as e.g. an exciton blocking layer between the emission layer and an electrode.
- a PLED is an OLED containing one or more polymers in the emission layer.
- the polymers are typically processed from solution.
- One possible layer sequence for PLEDs is the following: anode / HIL or buffer layer / interlayer / EML / cathode.
- the interlayer has both hole transport and electron blocking properties. Further details of INterlayer in PLEDs are disclosed in WO 2004/084260 A2.
- Organic light-emitting electrochemical cells (OLECs) contain two electrodes and a mixture of an electrolyte and photoluminescent species between the electrodes (Pei et al., Science 1995, 269, 1086).
- OLECs and OLEDs have some similarities in their layered structure. However, OLECs have advantages in the selection of potential materials for the electrodes. Furthermore, the layers in OLECs can have a higher thickness. Overall, OLECs are easier to manufacture than OLEDs.
- the light sources mentioned may contain any further material that would be considered by the person skilled in the art. These materials can be color converters or color filters.
- the devices may contain down conversion materials.
- the color converters may be organic or inorganic materials. Color converters can be selected from the group of phosphor materials used in fluorescent displays or lamps or CRTs (cathode ray tubes).
- the light source itself can either emit light or radiation of a specific wavelength or a specific wavelength range or light of a specific pulse sequence continuously.
- the skilled person can adapt the pulse sequence depending on the therapeutic or cosmetic application.
- Particularly preferred skin lightening compound in the context of the present invention are selected from the group consisting of hydroquinone (, 4-dihydroxybenzene), kojic acid, arbutin, aloesin,
- Niacinamide Vitamin C and derivatives of Vitamin C, Rucinol, Plant extracts from Morus alba, Phyllanthus emblica or Eugenia uniflora.
- the radiation emitted by the radiation source can have any cosmetically and / or therapeutically useful wavelength or wavelength range.
- a preferred wavelength and / or a preferred wavelength range for the purposes of the present invention is in the range between 250 and 2000 nm, more preferably between 270 and
- 1800 nm more preferably emitted between 290 and 1600 nm, very particularly preferably between 300 and 900 nm and particularly preferably between 400 and 550 nm.
- the wavelength or the wavelength range can be selected by the person skilled in the art without any inventive step in each case in an application-specific manner.
- Already assignments between wavelengths and phototherapeutic applications are well known in the art. The following are some of these known assignments, without being limiting. They also represent preferred wavelengths or ranges of wavelengths, which are derived from the
- Radiation source can be emitted: Psoriasis - 290 to 330 nm, in particular 3 1 nm;
- a further subject of the present invention is the combination of at least one skin-lightening compound and at least one compound which has light-protection properties, for example UV / VIS / IR filters, for the therapeutic and / or cosmetic treatment of the skin with simultaneous application of phototherapy.
- a skin-lightening compound and at least one compound which has light-protection properties, for example UV / VIS / IR filters, for the therapeutic and / or cosmetic treatment of the skin with simultaneous application of phototherapy.
- an artificial radiation source is used.
- additional sunscreen filters care should be taken when selecting them to absorb radiation, but not phototherapeutic radiation.
- the additional use of substances with photoprotective properties has the effect that the effect of the phototherapy according to the invention can be further increased.
- the compounds with photoprotective properties prevent or reduce the tanning of the skin and thus make the skin more permeable to the phototherapeutic radiation.
- Another object of the present invention relates to pharmaceutical composition
- pharmaceutical composition comprising at least one skin-lightening compound and optionally at least one further pharmaceutical excipient.
- the pharmaceutical composition according to the invention preferably contains 4, more preferably 3, most preferably 2 and especially preferably exactly one skin-lightening compound and optionally at least one further pharmaceutical excipient.
- compositions which, in addition to the at least one skin lightening compound and in addition to optionally at least one further
- composition still contains at least one other active ingredient. It is preferred in this case that the composition contains exactly one skin-lightening compound and 3, more preferably 2 and very particularly preferably exactly one further active ingredient.
- compositions pharmaceutical formulations
- “Pharmaceutical preparation” here is any agent which can be used in the prophylaxis, therapy, follow-up or treatment of patients who show at least temporarily a pathogenic modification of the overall state or condition of individual parts of the patient's organism, preferably from disorders of the skin
- Another object of the present invention relates to cosmetic composition containing at least one skin lightening
- the cosmetic composition according to the invention preferably contains 4, more preferably 3, very preferably 2 and particularly preferably exactly one skin-lightening compound and optionally at least one further cosmetic adjuvant.
- the present invention relates to cosmetic compositions, in addition to the at least one skin-lightening compound and in addition to the optionally at least one other
- cosmetic adjuvant still contains at least one other active ingredient.
- the composition contains exactly one skin-lightening compound and 3, more preferably 2 and very particularly preferably exactly one further active ingredient.
- the cosmetic compositions may also contain at least one other active ingredient
- the further active ingredient is preferably used in the same composition in which the skin lightening compound is present.
- the further active ingredient and the skin lightening compound are present in separate dosage forms.
- the further active ingredient is administered orally, whereas the skin-lightening compound is applied topically by means of a cream, ointment, lotion, emulsion, etc.
- the other active ingredient for the cosmetic or pharmaceutical is the cosmetic or pharmaceutical
- Compositions is preferably selected from the group of antioxidants, vitamins, UV filters, light filters (VIS, IR), anti-inflammatory
- Active ingredients anti-aging agents (anti-aging agents) and anti-cellulite agents.
- the use is in combination with at least one or more UV filters.
- the further active ingredient is selected from the group of dermatologically used active ingredients.
- these include in particular the corticoids, glucocorticoids (for example cortisone, corticosterone and cortisol), mineral corticoids (for example aldosterone and desoxycorticosterone), synthetic corticoids (for example prednisone and prednisolone, methyl prednisolone, triamcinolone, dexamethasone, betamethasone and para-methasone).
- photodynamic agents can be used as further active ingredients.
- photodynamic agents include, for example, porphyrins, chlorophylls, and dyes, aminolevulinic acid, methyl-aminolevulinate, levulinic acid, silicone phthalocyanine, m-tetrahydroxyphenylchlorin, and mono-L-aspartyl-chlorin, Photofrin® sodium porfirmer, Visudyne® (verteporfin), Foscan® (Temoporfin ), Metvix® (methyl (5-amino-4-oxopentanoate)), Cysview TM (hexaminolevinic acid), Laserphyrin® (talaporfin), photochloro (2- (1-hexyloxyethyl) -2-devinylpyropheophorbide-a (HPPH)) , Photrex® (Rostaporfin), psoralen (eg 8-methoxy-p
- composition is used synonymously also the term “agent”, “preparation” or “formulation”.
- compositions of the present invention are usually topically applicable compositions, e.g. cosmetic or pharmaceutical or dermatological formulations or medical devices.
- Topically applicable means for the purposes of the invention that the preparation is applied externally and locally, i. that the preparation must be suitable, for example, to be applied to the skin can.
- the preparations in this case contain a cosmetically, pharmaceutically or dermatologically suitable carrier and, depending on the desired property profile, optionally further suitable ingredients.
- compositions may comprise, contain, consist essentially of or consist of the necessary or optional ingredients mentioned above and / or below. Any compounds or components which may be used in the compositions are either known and commercially available or may be synthesized by known methods.
- compositions of the invention preferably contain from 0.01% to 99% by weight of the skin lightening compound, based on the total weight of the composition. Preference is given to using an amount of from 0.05 to 30% by weight, more preferably from 0.1 to 10% by weight. It prepares the expert no difficulties the quantities depending on the to select the intended effect of the composition accordingly.
- UV filters can be used in the pharmaceutical, cosmetic and dermatological compositions according to the invention. Particularly preferred are those UV filters, dereri physiological harmlessness is already demonstrated. Both for UVA and UVB filters, there are many known and proven substances from the literature. The compounds listed in the following lists are to be considered as examples only. Of course, other UV filters can be used.
- Preferred formulations may contain organic UV filters, so-called hydrophilic or lipophilic sunscreen filters, which are in the UVA range and / or UVB range and / or IR and / or VIS range
- ABSOR Absorber
- These substances can be used in particular under p-aminobenzoic acid derivatives, salicylic acid derivatives, .beta., .Beta.-diphenyl acrylate derivatives, camphor derivatives, triazine derivatives, cinnamic acid derivatives and polymeric filters and silicone filters described in the application
- WO 93/04665 are selected. Further examples of organic filters are given in patent application EP-A 0 487 404. In the following, the named UV filters are usually named according to the INCI nomenclature.
- para-aminobenzoic acid and its derivatives PABA, ethyl PABA, ethyl dihydroxypropyl PABA, ethylhexyl dimethyl PABA, for example, sold under the name "Escalol 507" from the company ISP, glyceryl PABA, PEG-25 PABA, For example, sold under the name "Uvinul P25” from BASF.
- Salicylates homosalates sold under the name "Eusolex HMS” by Merck; Ethylhexyl salicylate, for example sold under the name "Neo Heliopan OS" from the Fa.
- Benzophenone-1 e.g. distributed under the
- Benzylidene camphor derivatives 3-Benzylidene camphor, e.g. sold under the name "Mexoryl SD” of the company Chimex; 4-methylbenzylidene camphor, e.g. sold under the name “Eusolex 6300” by Merck; Benzylidene camphorsulfonic acid, e.g. sold under the name “Mexoryl SL” by Chimex; Camphor benzalkonium methosulfates, e.g. sold under the name "Mexoryl SO” by Chimex;
- Terephthalylidenedicamphorsulfonic acid for example sold under the name "Mexoryl SX” from the Fa Chimex; Polyacrylamidomethylbenzylidene camphor, sold under the name “Mexoryl SW” from Chimex.
- Phenylbenzimidazole derivatives phenylbenzimidazole sulfonic acid, e.g.
- Phenylbenzotriazole derivatives Drometrizol trisiloxanes, e.g. sold under the name "Silatrizole” by the company Rhodia Chimie; Methylenebis (benzotriazolyl) tetramethylbutylphenol in solid form, e.g. sold under the name "MIXXIM BB / 100" by the company Fairmount Chemical, or in micronized form as an aqueous dispersion, e.g. sold under the name "Tinosorb M” by BASF.
- Triazine derivatives ethylhexyltriazone, e.g. sold under the name "Uvinul T150" from BASF; Diethylhexylbutamidotriazone, e.g. marketed under the name “Uvasorb HEB” by the company Sigma 3V; 2,4,6-tris (diisobutyl 4'-aminobenzalmalonate) -s-triazines or 2,4,6-tris (biphenyl) -1, 3,5-triazines, sold as Tinosorb A2B by BASF ; 2,2 '- [6- (4-methoxyphenyl) -1, 3,5-triazine-2,4-diyl] bis [5- (2-ethylhexyl) oxy] phenol, sold as Tinosorb S from the company.
- Anthraniline derivatives menthyl anthranilate, e.g. sold under the name "Neo Heliopan MA" by Fa. Symrise.
- Imidazole derivatives ethylhexyldimethoxybenzylidenedioxoimidazoline propionate.
- Benzalmalonate Derivatives Polyorganosiloxanes containing functional benzalmalonate groups, such as polysilicone-15, for example sold under the name "Parsol SLX" by Hoffmann LaRoche.
- 4,4-Diarylbutadiene derivatives 1,1-dicarboxy (2,2'-dimethylpropyl) -4,4-diphenylbutadiene.
- Benzoxazole Derivatives 2,4-bis [5- (1-dimethylpropyl) benzoxazol-2-yl (4-phenyl) imino] -6- (2-ethylhexyl) imino-1,3,5-triazines, e.g. sold under the name Uvasorb K2A from the company Sigma 3V and mixtures thereof containing.
- Suitable organic UV-protective substances are preferably selected from the following list: ethylhexyl salicylate, phenylbenzimidazole-sulphonic acid, benzophenone-3, benzophenone-4, benzophenone-5, n-hexyl 2- (4-diethylamino-2-hydroxybenzoyl) benzoate, 4 Methylbenzylidene camphor, terephthalylidenedicamphorosulfonic acid, disodium phenyldi- benzimidazole tetrasulfonate, methylenebis (benzotriazolyl) tetramethylbutylphenol, ethylhexyltriazone, diethylhexylbutamidotriazone, dromethtrizole trisiloxanes, polysilicone-15,1,1-dicarboxy- (2,2'-dimethylpropyl) -4,4 - Diphenylbutadiene, 2,4
- organic UV filters are usually incorporated in an amount of 0.01 to 20 wt .-%, preferably 1 to 20 wt .-%, in formulations.
- the preparations may contain, in addition to the extract and the optionally organic UV filters, as described above, further inorganic UV radiation. Filters, so-called particulate UV filters included. These combinations with particulate UV filters are possible both as a powder and as a dispersion or paste of the following types.
- coated titanium dioxide for example Eusolex ® T-2000, Eusolex ® T-AQUA, Eusolex ® T-AVO, Eusolex ® T-OLEO), zinc oxides (for example Sachtotec® ®),
- Iron oxides or else cerium oxides and / or zirconium oxides are preferred.
- pigmentary Titandixoxid or zinc oxide are possible, wherein the particle size of these pigments is greater than or equal to 200 nm, for example ® Hombitan FG or Hombitan ® FF Pharma.
- the preparations may further be preferred if the preparations contain inorganic UV filters which are prepared by customary methods, such as, for example, in US Pat
- Cosmetics & Toiletries 1990, 105, 53 have been post-treated. This may include one or more of the following
- Aftertreatment components may be chosen: amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids,
- Lecithin phospholipids, sodium, potassium, zinc, iron or aluminum salts of fatty acids, polyethylenes, silicones, proteins (especially
- Collagen or elastin alkanolamines, silica, alumina, other metal oxides, phosphates, such as sodium hexametaphosphate or glycerol.
- Preferably used particulate UV filters are:
- untreated titanium dioxides e.g. the products Microtitanium Dioxide MT 500 B from Tayca; Titanium Dioxide P25 from Degussa,
- Silica after-treatment such as the product "Microtitanium Dioxide MT 100 SA of Tayca; or the product “Tioveil Fin” from Uniqema,
- micronised titanium dioxides with alumina and / or aluminum stearates / laurate aftertreatment such as e.g. Microtitanium ium Dioxide MT 100 T from Tayca, Eusolex T-2000 from Merck,
- Iron stearates aftertreatment such as e.g. the product "Microtitanium Dioxide MT 100 F" from Tayca,
- Alumina and silicone aftertreatment such as e.g. the product "Microtitanium Dioxide MT 100 SAS", the company Tayca,
- Sodium hexameta-phosphates e.g. the product "Microtitanium Dioxide MT 150 W” from Tayca.
- the treated micronized titanium dioxides used for combination may also be post-treated with:
- Alumina and stearic acid such as. the product UV-Titan M160 of the company Sachtleben,
- Aluminum and silicone oils e.g. the product UV-Titan M262 of the company Sachtleben,
- Polydimethylsiloxanes e.g. the product 70250 Cardre UF Ti02SI3 "from the company Cardre,
- Escalol Z100 from ISP (alumina aftertreated ZnO dispersed in an ethylhexyl methoxycinnamate / PVP hexadecenes /
- Fuji ZNO-SMS-10 from Fuji Pigment (ZnO aftertreated with silica and polymethylsilsquioxane);
- mixtures of different metal oxides for example titanium dioxide and cerium oxide with and without after-treatment, such as, for example, the product Sunveil A from Ikeda.
- mixtures of aluminum oxide, silicon dioxide and silicon-treated titanium dioxide / zinc oxide mixtures for example the product UV-Titan M261 from Sachtleben.
- These inorganic UV filters are usually incorporated in an amount of 0.1 to 25 wt .-%, preferably 2 to 10 wt .-%, in the preparations.
- UV filters can also be used in encapsulated form.
- the capsules in preparations to be used according to the invention are preferably present in amounts which ensure that the encapsulated UV filters are present in the preparation in the above-indicated weight percentages.
- sunscreen filters which absorb light in the wavelength range from 400 to 800 nm (VIS) and in the infrared wavelength range (IR) from 800 nm.
- VIS VIS
- IR infrared wavelength range
- sunscreen filters absorb light from said wavelength ranges, but not the therapeutic wavelength, so that the therapeutic light can reach the site of action in the skin without being absorbed.
- Common sunscreen filters are disclosed in EP 0898955 A2.
- light protection filters can be pigments which are reflecting and / or absorbing (VIS-reflecting) pigments and / or dyes in the visible wavelength range.
- Such pigments may be, in particular, golden, red, orange, copper or body-colored interference pigments, which are very similar to natural skin color.
- interference pigments are preferably
- platy or mottling mica with a diameter up to 15 ⁇ , which is coated with Sn0 2 and / or Ti0 2 .
- interference pigments are also suitable whose carrier material does not consist of mica.
- the coatings can be doped differently, such as by iron or cerium.
- these pigments is mica with a thin coating consisting of up to one wt .-% Sn0 2 , and a coating consisting of 50 to 70 wt .-%, preferably 54 to 60 wt .-% , Ti0 2 with a rutile structure.
- the light protection filters may also be mica with a thin coating consisting of up to one weight percent SnO 2 , and a coating consisting of 50 to 70 weight percent, preferably 54 to
- ⁇ 2 act with an anatase structure or mica with a coating consisting of 50 to 70 wt .-%, preferably 54 to 60 wt .-%, ⁇ 2 with a rutile or anatase structure.
- Suitable substances which can also be used as VIS and / or as IR filters are pearlescent pigments, consisting of mica or other support materials which are coated with titanium dioxides or iron oxides, in particular these are
- Silver pigments (mica + Ti0 2 ) with particle sizes ⁇ 200 ⁇ , in particular ⁇ 15 ⁇ , such as the commercially available Timiron MP 1005 TM or MP 1001 TM or coarser fractions
- Interference pigments (mica + Ti0 2 ) with particle sizes ⁇ 200 ⁇ , in particular with particle sizes of 5 to 25 ⁇ , with golden, red, orange, copper or body-colored interference, such as Timiron Silk Red TM or Silk Gold TM or Super Red TM or Super Gold TM or Super Copper TM or coarser fractions or other interference colors and mixtures thereof
- Gold pigments (mica + Ti0 2 and iron oxides) with particle sizes ⁇ 200 ⁇ , in particular ⁇ 5 to 25 ⁇ or ⁇ 5 ⁇ ; such
- Gold pigment is e.g. Timiron MP 20 TM, but also coarser
- Color pigments (mica + Ti0 2 and iron oxides) with particle sizes ⁇ 200 ⁇ , in particular ⁇ 5 to 25 ⁇ or ⁇ 15 ⁇ ; appropriate
- Color pigments are e.g. Dichrona TM or Microna TM mat.
- VIS absorbing or reflecting fillers such as mica coated with Ti0 2 and / or BaS0. 4
- VIS absorbing or reflecting fillers such as mica coated with Ti0 2 and / or BaS0. 4
- VIS absorbing or reflecting fillers such as mica coated with Ti0 2 and / or BaS0. 4
- Biron TM BiOCI
- Low Luster TM Low Luster TM
- Extender W TM unless they are 100% transparent
- Pearlescent pigments Pearlescent pigments, VIS-reflecting or absorbing fillers or dyes.
- microfine ZnO and Ti0 2 particles are suitable as such, provided that they also reflect or absorb in the VIS range.
- These are commercially available under the names Hombitec TM or Sachotec TM, Kemira M160 TM, Tioveil AQ TM and, to a limited extent, Eusolex T-2000 TM limited since it has a very high transparency.
- Suitable VIS filters may also be dyes approved in cosmetics, for example selected from the "Blue List” (List of Cosmetic-Permitted Dyes) ["Blue List” Edition Cantor Verlag, Ed. HP Fiedler (1993)], which is hereby incorporated by reference can be used as such as well as in a mixture. These dyes can also be used as undissolved pigments. Particularly suitable here are the red, yellow and blue dyes which, individually or in a mixture with the other additives, lead to formulations which show a natural color when applied to the skin. Therefore, dyes of this list can also be used with colors other than those mentioned, e.g. orange or gold.
- red dyes of the name D & C Red Preferably used as red dyes of the name D & C Red, preferably with the numbers no. 10, Cl 15630, no. 7, Cl 15850 and no. 21, Cl 45380, Acid Red, preferably Acid Red No. 1, Cl 18050, Allura Red, trans-alpha, beta or gamma-carotene, Pigment Red.
- Yellow dyes are those with the name Acid Yellow, preferably Acid Yellow No. 1, Cl 10316, Tartrazine, Cl 19140, Rutin, D & C Yellow No. 7, Cl 45350, Disperse Yellow, Food Yellow, Natural Yellow, Pigment Yellow, Solvent Yellow.
- Corresponding blue dyes are Acid Blue, preferably Acid Blue No. 9, C.I. 42090, Acid Blue No. 80, C.I. 61585, D & C Blue no. 6, C.I. 73000, C-Blue 21, Direct Blue 86.
- VIS-absorbing substances are also suitable, such as e.g. Flavonoids or natural or artificial melanin.
- the VIS filters can also have a protective effect in the UV or IR range.
- pigments which are reflective in the IR range are used.
- the strong "Weissein" on the skin is considered to be in need of improvement. This problem is solved by providing a new Inteferenzpigmentes with effect in the IR wavelength range.
- This interference pigment consists of platelet-shaped or
- milled mica which is coated with T1O2 different layer thicknesses, and which also be doped with iron or cerium can.
- the interference pigments have tints in the range of coppery, yellowish and skin-pink.
- the shades can also be given according to codes from the "Pantone Color Formula Guide 1000" which are known to the person skilled in the art.
- the pigments show a white body color, i. the formulations have a white color, but then a copper or skin-pink interference color appears on the skin as desired. The unwanted "wisdom” does not occur here.
- the preparation of the interference pigments is carried out according to the generally known methods for the continuous layer structure of Ti (OH) 4 on mica particles (for example described in the documents US 4,038,099, DE-PS 25 22 572 or also EP 0 271 767 B1). The process is then stopped at the desired interference color.
- the particle size is of high importance for the effectiveness. Very particular preference is given to a particle size of from 5 to 25 ⁇ m, since an optimum protective effect against the IR radiation can thus be achieved.
- this interference pigment can also be excellently suitable for the VIS range.
- the interference pigments for the VIS range can also be produced, for example, according to the methods described in the cited documents.
- the filters for protection against VIS and IR radiation can each in concentrations of 0.5 to 20 wt .-%, preferably 3 to 10 wt .-%, in cosmetic formulations are incorporated. These are substances which are easily dissolved, dispersed or emulsified with water and oils.
- the sunscreen filters can be directly without further preparatory
- At least one further active ingredient can be present in the preparations according to the invention.
- the further active ingredient is preferably selected from the group of UV filters, antioxidants, vitamins, skin-lightening active ingredients, anti-aging agents, anti-inflammatory agents, antimicrobial agents, agents for improving the moisture content of the skin (skin moistness regulators), anti-cellulite Active ingredients, anti-wrinkle agents, anti-dandruff agents, anti-acne agents, deodorants, pigments and self-tanning substances, more preferably from the group of UV filters, antioxidants, vitamins, anti-aging agents and anti-cellulites Active ingredients, most preferably from the group of UV filters, antioxidants, vitamins and skin lightening agents.
- Preparation of at least one substance which serves to maintain and / or improve the moisture content of the skin may, without being construed as limiting, include substances that belong to the so-called natural moisturizing factors, such as.
- the preparation contains one or more antioxidants and / or one or more vitamins.
- Radicals are achieved in general, wherein the expert no It is difficult to select suitable fast or delayed-acting antioxidants.
- antioxidants for example amino acids (eg glycine, histidine, tyrosine, tryptophan) and their derivatives, and their derivatives, peptides, such as D, L-carnosine, D- Carnosine, L-carnosine and their derivatives (eg, anserine), carotenoids, carotenes (such as ⁇ -carotene, ⁇ -carotene, lycopene) and their derivatives, chlorogenic acid and its derivatives, urothioglucose, propylthiouracil and other thiols (such as thioredoxin, glutathione, cysteine , Cystine, cystamine and their glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, but
- Suitable antioxidants are also compounds of the general
- X is O or NH
- R 2 is linear or branched alkyl having 1 to 30 C atoms
- R 3 is linear or branched alkyl having 1 to 20 C atoms
- R H linear or branched alkyl having 1 to 8 carbon atoms or
- R e is linear or branched alkyl having 1 to 8 carbon atoms.
- RonaCare® AP RonaCare® AP
- antioxidants are also suitable for use in the formulations of the invention.
- Known and purchasable Mixtures are for example mixtures containing as active ingredients lecithin, L - (+) - ascorbyl palmitate and citric acid, natural tocopherols, L - (+) - ascorbyl palmitate, L - (+) - ascorbic acid and citric acid (such as Oxynex ® K LIQUID), tocopherol extracts from natural sources, L - (+) - ascorbyl palmitate, L - (+) - ascorbic acid and citric acid (for example Oxynex ® L LIQUID), DL-a-tocopherol, L - (+) - ascorbyl palmitate, citric acid and lecithin (for example Oxynex ® LM) or butylhydroxytoluene (BHT), L - (+) - ascorbyl palmitate and citric acid (such as Oxynex ® 2004).
- Such antioxidants are
- the polyphenols which are sometimes present as natural substances, are of particular interest for applications in the pharmaceutical, cosmetic or food sector.
- the flavonoids or bioflavonoids which are mainly known as plant dyes, frequently have an antioxidant potential.
- Lemanska et al., Current Topics in Biophysics 2000, 24 (2), 01-108 deal with effects of the substitution pattern of mono- and dihydroxy flavones. It is observed there that dihydroxyflavones having an OH group adjacent to the keto function or OH groups in the 3'4- or 6,7- or 7,8-position have antioxidant properties, while other mono- and dihydroxyflavones partially no antioxidant
- Quercetin (cyanidanol, cyanidolone 1522, meietin,
- Sophoretine, ericin, 3,3 ', 4', 5,7-pentahydroxyflavone) as a particularly effective antioxidant eg Rice-Evans et al., Trends in Plant Science 1997, 2 (4), 152-159.
- Lemanska et al., Free Radical Biology & Medicine 2001, 31 (7), 869-881 investigate the pH dependence of the antioxidant action of hydroxyflavones. Quercetin shows the highest activity of the investigated structures over the entire pH range.
- the preparations according to the invention may contain vitamins as further ingredients. Preference is given to vitamins and vitamin derivatives selected from vitamin A, vitamin A propionate, vitamin A palmitate, vitamin A acetate, retinol, vitamin B, thiamin chloride hydrochloride (vitamin Bi), riboflavin (vitamin B 2 ), nicotinamide, Vitamin C (ascorbic acid), vitamin D, ergocalciferol (vitamin D 2 ), vitamin E, DL-a-tocopherol, tocopherol-E-acetate, tocopherol hydrogen succinate, vitamin K1, esculin (vitamin P active ingredient), thiamine (vitamin B ⁇ , Nicotinic acid (niacin),
- Preparations contain, in particular preferably vitamin A palmitate, vitamin C and its derivatives, DL-a-tocopherol, tocopherol E acetate, nicotinic acid, pantothenic acid and biotin.
- Vitamins are usually added to the formulations when applied cosmetically in the range of 0.01% to 5% by weight, based on the total weight.
- the preparations according to the invention may additionally contain anti-aging active ingredients, anti-cellulite active ingredients or conventional skin-friendly or skin-care active ingredients.
- Skin-sparing or skin-care active ingredients can, in principle, be all active ingredients known to the person skilled in the art.
- Particularly preferred anti-aging active ingredients are pyrimidinecarboxylic acids, aryloximes, bioflavonoids, bioflavonoid-containing extracts, chromones or retinoids.
- Suitable anti-aging ingredients especially for skin care
- Preparations are preferably also so-called compatible solutes. These are substances that are involved in the osmoregulation of Plants or microorganisms are involved and can be isolated from these organisms. Under the generic term compatible solutes also the described in the German patent application DE-A-10133202 osmolytes are taken. Suitable osmolytes are, for example, the polyols, methylamine compounds and amino acids and in each case their precursors.
- osmolytes are understood as meaning, in particular, substances from the group of the polyols, such as, for example, myo-inositol, mannitol or sorbitol and / or one or more of the osmolytically active substances mentioned below: taurine, choline, Betaine, phosphorylcholine, glycerophosphorylcholines, glutamine, glycine, a-alanine, glutamate, aspartate, proline, and taurine.
- Precursors of these substances are, for example, glucose, glucose polymers, phosphatidylcholine, phosphatidylinositol, inorganic phosphates, proteins, peptides and polyamine acids.
- Precursors are, for example, compounds that are converted into osmolytes by metabolic steps.
- solute substances are selected from the group consisting of pyrimidinecarboxylic acids (such as ectoine and hydroxyectoine), proline, betaine, glutamine, cyclic diphosphoglycerate, N-acetylornithine, trimethylamine-N-oxide, di-myo-inositol-phosphate (DIP).
- pyrimidinecarboxylic acids such as ectoine and hydroxyectoine
- proline such as proline
- betaine glutamine
- cyclic diphosphoglycerate glutamine
- N-acetylornithine N-acetylornithine
- trimethylamine-N-oxide di-myo-inositol-phosphate (DIP).
- DIP di-myo-inositol-phosphate
- cyclic 2,3-diphosphoglycerate (cDPG), 1, 1-diglycerol phosphate (DGP), ⁇ -mannosylglycerate (firoin), ⁇ -mannosylglyceramide (Firoin-A) or / and di-mannosyl-di-inositolphosphate (DMIP) or an optical isomer, derivative, eg an acid, a salt or ester of these compounds or combinations thereof.
- ectoine (S) -1,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid) and hydroxyectoine ((S, S) -1,4,5,6-tetrahydro-5 are among the pyrimidinecarboxylic acids hydroxy-2-methyl-4-pyrimidinecarboxylic acid) and their derivatives.
- Known anti-aging substances are also chromones, as described for example in EP 1508327 or retinoids, for example retinol (vitamin A), retinoic acid, retinaldehyde or synthetically modified compounds of vitamin A.
- the described chromones and retinoids are also effective anti-cellulites -Wirkstoffe.
- Another well-known anti-cellulite drug is caffeine.
- preparations according to the invention e.g. called: solutions, suspensions, emulsions, PIT emulsions, pastes, ointments, gels, creams, lotions, powders, soaps, surfactant-containing cleaning preparations, oils, aerosols, patches, envelopes, dressings and sprays, especially for external use.
- Other applications are e.g. Sticks, shampoos and shower baths.
- Further typical cosmetic application forms are also lipsticks, lip balms, powder, emulsion and wax make-up as well as sunscreen, pre-sun and after-sun preparations.
- Cosmetic and dermatological preparations according to the invention may in particular be an anhydrous preparation, a lotion or emulsion, such as cream or milk, or microemulsion, in each case of the water-in-oil (W / O) or of the oil-in-water type (O / W ), a multiple emulsion, for example of the type Waser-in-oil-in-water (W / O / W) or vice versa (O / W / O), gels or solutions (especially oily-alcoholic, oily-aqueous or aqueous alcoholic gels or solutions), a solid stick, an ointment or even an aerosol.
- the cosmetic and dermatological preparations according to the invention are applied to the skin in a sufficient amount in the manner customary for cosmetics.
- An embodiment of the invention is an emulsion which is present as a cream or milk and for example fatty alcohols, fatty acids, fatty acid esters, in particular triglycerides of fatty acids, lanolin, natural and synthetic oils or waxes and emulsifiers in the presence of Contains water.
- a particularly preferred preparation of the invention may also be present as an alcoholic gel containing one or more lower alcohols or polyols, such as ethanol, propylene glycol or glycerol, and a thickening agent , such as silica.
- the oily-alcoholic gels also contain natural or synthetic oil or wax.
- the solid sticks are preferably made of natural or synthetic waxes and oils, fatty alcohols, fatty acids, fatty acid esters, lanolin and other fatty substances. If a preparation is formulated as an aerosol, the usual blowing agents are preferably used, such as alkanes, air, nitrogen, dinitrogen monoxide, particularly preferably alkanes or air.
- any customary carrier substances, adjuvants and optionally further active ingredients can be added to the preparation.
- Preferable excipients come from the group of preservatives, stabilizers, solubilizers, colorants, i. Pigments, dyes, emulsifiers or odor improvers.
- the present invention accordingly also provides preparations, which contain a carrier suitable for cosmetic, pharmaceutical or / and dermatological applications and optionally physiologically acceptable excipients and / or fillers.
- Ointments, pastes, creams and gels may contain the usual excipients suitable for topical administration, such as
- Powders and sprays may contain the usual carriers, e.g. Lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances.
- Sprays may additionally contain the usual volatile, liquefied propellants, e.g. Chlorofluorocarbons, propane / butane or dimethyl ether.
- compressed air is advantageous to use.
- air can also be used in non-pressurized metering devices, such as e.g. Pump sprays, are used.
- Solutions and emulsions may contain the usual excipients such as solvents, solubilizers and emulsifiers, e.g. Water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylglycol, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol fatty acid esters, polyethylene glycols and fatty acid esters of sorbitan or mixtures contain these substances.
- solvents e.g. Water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylglycol, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, gly
- a preferred solubilizer in general is 2-isopropyl-5-methylcyclohexanecarbonyl-D-alanine methyl ester.
- Suspensions may be the usual carriers such as liquid
- Diluents such as water, ethanol or propylene glycol, suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.
- Soaps may contain the usual excipients such as alkali metal salts of fatty acids, salts of fatty acid monoesters, fatty acid protein hydrolysates, isothionates, lanolin, fatty alcohol, vegetable oils, plant extracts, glycerol, sugars or mixtures of these substances.
- Surfactant-containing cleaning products may include the usual excipients such as salts of fatty alcohol sulfates, fatty alcohol ether sulfates, sulfosuccinic monoesters, fatty acid protein hydrolysates, isothionates, imidazolinium derivatives, methyl taurates, sarcosinates, fatty acid amide ether sulfates, alkyl amidobetaines, fatty alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable and synthetic oils, lanolin derivatives, ethoxylated glycerol - Contain fatty acid esters or mixtures of these substances.
- excipients such as salts of fatty alcohol sulfates, fatty alcohol ether sulfates, sulfosuccinic monoesters, fatty acid protein hydrolysates, isothionates, imidazolinium derivatives, methyl taurates, sarcosinate
- Facial and body oils may contain the usual excipients such as synthetic oils such as fatty acid esters, fatty alcohols, silicone oils, natural oils such as vegetable oils and oily vegetable extracts, paraffin oils, lanolin oils or mixtures of these substances.
- synthetic oils such as fatty acid esters, fatty alcohols, silicone oils, natural oils such as vegetable oils and oily vegetable extracts, paraffin oils, lanolin oils or mixtures of these substances.
- the preferred preparation forms according to the invention include in particular emulsions.
- O / W emulsions become special
- Emulsions, W / O emulsions and O / W emulsions are available in the usual way.
- Emulsions of the invention are advantageous and contain e.g. the said fats, oils, waxes and others
- Fat body and water or an aqueous phase, for example with solvents or hydrophilic surfactants, and an emulsifier, as it is usually used for such a type of preparation.
- Oils such as triglycerides of capric or caprylic acid, also natural oils such. Castor oil; Fats, waxes and other natural and synthetic fatty substances, preferably esters of fatty acids with alcohols of low C number, for example with isopropanol, propylene glycol or glycerol, or esters of fatty alcohols with alkanoic acids of low C number or with fatty acids;
- Silicone oils such as dimethylpolysiloxanes, diethylpolysiloxanes, diphenyl polysiloxanes and mixed forms thereof.
- the oil phase of the emulsions, oleogels or hydrodispersions or lipodispersions in the context of the present invention is advantageously selected from the group of esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids having a chain length of 3 to 30 carbon atoms and saturated and / or or unsaturated, branched and / or unbranched alcohols having a chain length of 3 to 30 carbon atoms, from the group of esters of aromatic carboxylic acid and saturated and / or unsaturated, branched and / or unbranched alcohols having a chain length of 3 to 30 carbon atoms.
- ester oils can then advantageously be selected from the group isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-ethylhexyl laurate, 2-hexadecyl stearate , 2-octyldodecyl palmitate, oleyl oleate, oleyl erucate, erucyl oleate, erucyl erucate and synthetic, semi-synthetic and natural mixtures of such esters, such as jojoba oil.
- the oil phase can be advantageously selected from the group of branched and unbranched hydrocarbons and waxes, silicone oils, dialkyl ethers, the group of saturated or unsaturated, branched or unbranched alcohols, and fatty acid triglycerides, namely the triglycerol esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids of a chain length of 8 to 24, in particular 12-18 C-atoms.
- the fatty acid triglycerides can be selected, for example, advantageously from the group of synthetic, semi-synthetic and natural oils, for.
- Olive oil sunflower oil, soybean oil, terrestrial nut oil, rapeseed oil, almond oil, palm oil, coconut oil, palm kernel oil and the like. Any mixtures of such oil and wax components are also advantageous to use in the context of the present invention. It may also be advantageous, if appropriate, to use waxes, for example cetyl palmitate, as the sole lipid component of the oil phase.
- the aqueous phase of the preparations according to the invention advantageously contains alcohols, diols or polyols of low C number, and their ethers, preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl, monoethyl or monobutyl ether, diethylene - Glykolmonomethyl- or -monoethylether and analogous products, also low C-number alcohols, such as Ethanol, isopropanol, 1,2-propanediol, glycerol, and in particular one or more thickening agents, which may be advantageously selected from the group of silicon dioxide, aluminum silicates, polysaccharides or their derivatives, e.g.
- Hyaluronic acid, xanthan gum, hydroxypropylmethylcellulose particularly advantageous from the group of polyacrylates, preferably a polyacrylate from the group of so-called Carbopols, for example Carbopols types 980, 981, 1382, 2984, 5984, each individually or in combination.
- Carbopols for example Carbopols types 980, 981, 1382, 2984, 5984, each individually or in combination.
- mixtures of the abovementioned solvents are used.
- water can be another ingredient.
- the preparations according to the invention contain hydrophilic surfactants.
- the hydrophilic surfactants are preferably selected from the group of alkylglucosides, acyl lactylates, betaines and cocoamphoacetates.
- emulsifiers for example, the known W / O and ⁇ / V emulsifiers can be used. It is advantageous to use other common co- To use emulsifiers in the preferred O / W emulsions according to the invention.
- suitable co-emulsifiers are, for example, O / W emulsifiers, primarily from the group of substances having HLB values of 11-16, very particularly advantageously having HLB values of 14.5-15.5, if the ⁇ / V emulsifiers have saturated radicals R and R '. If the O / W emulsifiers have unsaturated radicals R and / or R ', or if isoalkyl derivatives are present, the preferred HLB value of such emulsifiers may also be lower or higher.
- fatty alcohol ethoxylates from the group of ethoxylated stearyl alcohols, cetyl alcohols, cetylstearyl alcohols (cetearyl alcohols).
- Polyethylene glycol (12) isostearate, polyethylene glycol (13) isostearate,
- Polyethylene glycol (14) isostearate, polyethylene glycol (15) isostearate,
- Polyethylene glycol (24) isostearate, polyethylene glycol (25) isostearate,
- Polyethylene glycol (20) to choose sorbitan monooleate
- W / O emulsifiers can be used:
- W / O emulsifiers are glyceryl monostearate, glyceryl, glyceryl monomyristate, glyceryl di- glyceryl stearate Diglycerylmonoisostearat, propylene glycol, propylene glycol monoisostearate alcohol, propylene glycol monocaprylate, propylene glycol, sorbitan, sorbitan, sorbitan, Sorbitanmonoisooleat, sucrose, cetyl, stearyl, arachidyl, Behenyl alcohol, isobehenyl alcohol, selachyl alcohol, chimyl alcohol, polyethylene glycol (2) stearyl ether (steareth-2), glyceryl monolaurate, glyceryl monocaprinate, glyceryl mono- caprylate or PEG-30 dipolyhydroxystearate.
- W / O emulsifiers are glyceryl monostearate, g
- the preparation may contain cosmetic adjuvants which are commonly used in this type of preparations, e.g.
- Thickening agents emollients, humectants, surfactants, emulsifiers, preservatives, antifoaming agents, perfumes, waxes, lanolin, propellants, dyes and / or pigments which color the agent itself or the skin, and other ingredients commonly used in cosmetics. It is possible to use as dispersion or solubilizing agent an oil, wax or other fatty substance, a low monoalcohol or a low polyol or mixtures thereof. Particularly preferred monoalcohols or polyols include ethanol, i-propanol,
- the mixing may result in dissolution, emulsification or dispersion of the active ingredients in the carrier.
- compositions according to the invention can be added.
- any substance that is compatible with the skin-lightening compounds according to the invention can be added.
- adjuvants are, for example, aluminum compounds such as aluminum hydroxide or aluminum phosphate, saponins such as QS 21,
- Muramyl dipeptide or muramyl tripeptide proteins, e.g. Gamma interferon or TNF, MF 59, phosphate dibylcholine, squalene or polyols.
- DNA encoding a protein with adjuvant effect can be administered in parallel or in a construct.
- the introduction of the pharmaceutical agent into a cell or an organism according to the invention can be done in any way that allows the melanin concentration to be reduced.
- the pharmaceutical agent of the present invention may be administered orally, topically, transdermally, transmucosally, transurethally, vaginally, rectally, pulmonarily, enterally and / or parenterally, preferably topically or transdermally.
- the chosen mode of administration depends on the indication, the dose to be administered, individual-specific parameters, etc. In particular, the various types of Administration site-specific therapy that minimizes side effects and reduces the drug dose.
- the dosage forms of the pharmaceutical agent are prepared with the usual solid or liquid carriers and / or diluents and the commonly used excipients according to the desired mode of administration in a suitable dosage and in a conventional manner.
- pharmaceutically acceptable excipients known to those skilled in the art may form part of the pharmaceutical composition of the invention, the amount of excipient material combined with the active ingredient to produce a single dosage varying with the individual to be treated and the mode of administration.
- pharmaceutically acceptable additives include salts, buffers, fillers, stabilizers, chelants, antioxidants, solvents, binders, lubricants, tablet coatings, flavors, colors, preservatives, sizing agents, and the like.
- excipients examples include water, vegetable oils, benzyl alcohols, alkylene glycol, polyethylene glycol, glycerol triacetate, gelatin, carbohydrates, e.g. Lactose or starch, magnesium stearate, talc and Vaseline.
- the pharmaceutical formulation may be in the form of tablet, film-coated tablet, dragee, lozenge, capsule, pill, powder, granule, syrup, juice, drops, solution, dispersion, suspension, suppository, emulsion, implant, cream, gel, ointment, paste, lotion, serum , Oil, spray, aerosol, glue, plaster or dressing.
- parenteral dosage forms such as suppositories, suspensions, emulsions, implants or solutions are to be considered, preferably oily or aqueous solutions.
- the medicinal product agent with at least one pharmaceutically acceptable carrier, such as microcrystalline cellulose, and optionally other excipients, such as moisturizers, applied to the skin solid formulations, such as creams, gels, ointments, pastes, powders or emulsions or to the skin formulated liquid formulations, such as solutions, suspensions, lotions, serums, oils, sprays or aerosols in a conventional manner.
- the pharmaceutical agent is for topical application.
- the pharmaceutical agent may also be presented as a solid composition, for example in the lyophilized state, and then prepared by the addition of a dissolving agent, such as distilled water, prior to use.
- a dissolving agent such as distilled water
- a “prophylactic effect” prevents the onset of a disease and includes an increase in the normal physiological function prophylaxis is particularly advisable when an individual has predispositions for the onset of the aforementioned diseases, such as a family history, a genetic defect or a recent Disease
- a "therapeutically relevant effect” partially or wholly relieves one, several or all disease symptoms or results in the partial or complete return of one or more or all of the physiological or biochemical parameters associated with or causative of the disease or pathological change , in the normal state.
- the particular dose or range of administration for the dose is large enough to achieve the desired prophylactic or therapeutic effect of inducing a biological or medical response. In general, the dose will vary with the age, constitution and gender of the patient, as well as the severity of the disease.
- the specific dose, frequency and duration of administration will depend on a variety of factors, such as the targeting and binding ability of the compounds, dietary habits of the individual to be treated, route of administration, excretion rate, and combination with other drugs.
- the individual dose can be adjusted both in relation to the primary illness and in relation to the occurrence of possible complications.
- the exact dose can be determined by a person skilled in the art by known means and methods.
- the pharmaceutical composition in order to promote the medicinal effect, may also comprise one or more further active ingredients, simultaneous or sequential administration being conceivable.
- kits consisting of a cited inventive cosmetic or pharmaceutical or dermatological composition and a device comprising an artificial radiation source which is selected from the group consisting of laser, lamp, light emitting diode (LED - light emitting diode); organic light emitting diode (OLED - organic light emitting diode), polymer light emitting diode (PLED - polymer light emitting diode) and organic light emitting electrochemical cell (OLEC, LEC or LEEC), preferably from lamp, LED, OLED, PLED and OLEC, most preferably from LED, OLED, PLED and OLEC and most preferably from OLED, PLED and OLEC.
- LED - light emitting diode organic light emitting diode
- OLED - organic light emitting diode organic light emitting diode
- PLED - polymer light emitting diode polymer light emitting diode
- OEC organic light emitting electrochemical cell
- the present invention also relates to a method for the cosmetic and / or therapeutic treatment of the skin, characterized in that the skin is treated by the combined use of at least one skin-lightening compound and by the irradiation by means of an artificial radiation source. Furthermore, the present invention also relates to a method for the cosmetic and / or therapeutic treatment of the skin, characterized in that the skin by the combined use of a Combination of at least one sunscreen and at least one skin lightening compound and is treated by the irradiation by means of an artificial radiation source.
- the combined use of compounds and radiation does not necessarily mean the simultaneous application of the two components.
- the application can be performed concurrently, overlapping in time or one after the other.
- the treatment method can be characterized in that the treatment of the skin with the skin-lightening compound and the irradiation take place in succession, overlapping or simultaneously.
- the skin, or parts thereof may, for example, be periodically treated and / or pretreated with the compositions described above. Typically, the skin must be pretreated to minimize melanin concentration during phototherapy.
- Treatment of the skin with the compound and the light source temporally overlapping and preferably occurs simultaneously.
- the invention uses the method for the pharmaceutical and / or cosmetic applications described in more detail above. Quite preferred is the treatment of jaundice, very particularly preferably jaundice of newborns and particularly preferably jaundice in neonates with the skin type III to VI.
- UV, VIS, IR sunscreen filters
- Steps to exclude each other This is especially true for preferred features of the present invention. Likewise, features of non-essential combinations can be used separately (and not in combination).
- Polymer IL1 which is used as an interlayer, is a copolymer containing the following two monomers with the mol% indicated in each case:
- the molecular weight (MW) of polymer 1L1 is distributed between 200,000 and 300,000 g / mol.
- BE1 is a copolymer containing 50% phenanthrene and 50% spirobifluorene units.
- the copolymer BE1 shows a broad
- the molecular weight (MW) of polymer BE1 is distributed between 200,000 and 300,000 g / mol.
- a formulation F1 is used which is prepared as follows:
- a solution A is prepared by dissolving BE1 in chloroform containing BE1 at a concentration of 10 mg / ml;
- Formulation 1 is obtained by mixing solutions A and B in a specific ratio so that the mass ratio of BE1: PEO: IM2 is equal to 1: 1: 0.2.
- OLEC1 with the layer sequence AI-cathode / EML / interlayer / PEDOT: PSS / ITO anode / substrate, wherein the emission layer (EML) contains BE1 can be prepared as follows.
- PEDOT (Baytron P AI 4083) is applied by means of spin coating in a thickness of 80 nm to the substrate and for 10 min. heated at 120 ° C.
- the substrate used is flexible polyethylene naphthalate (PEN); 150 nm of ITO are sprayed onto PEN;
- the emission layer EML (with a thickness of 300 nm) is through
- the device is at 120 ° C for 30 min. heated to remaining
- the device is cured by means of UV-cured resin (UV Resin T-
- the OLEC1 emits mainly light in the wavelength range between 400 and 500 nm. Through the use of filters or color converters, the emission can be adjusted to specific wavelengths depending on the application. To achieve emission at 466 nm, a filter is used.
- a PLED can also be made by methods well known to those skilled in the art.
- B16V mouse melanoma cells (manufacturer: DSMZ, article number: ACC370) in RPMI medium (Invitrogen, article no .: 31870), which additionally contains 10% FBS (Invitrogen, article no .: 10499044), 2 mM L Glutamine (Invitrogen, Art. No .: 25030) and 1 mM sodium pyruvate (Invitrogen, Cat. No. 11360) are added and incubated at 37 ° C and 5% C0 2 for 72 hours. The medium is separated and the cells are washed once with 10 ml of DPBS (Invitrogen, Item No. 14190) and then aspirated.
- RPMI medium Invitrogen, article no .: 31870
- FBS Invitrogen, article no .: 10499044
- 2 mM L Glutamine Invitrogen, Art. No .: 25030
- 1 mM sodium pyruvate Invit
- HyQtase-Cell Detachment Solution (Hyclone, article number SV30030.01) is added to the cells.
- the bottle is swiveled several times and the HyQtase- Cell Detachment Solution is then removed by suction. Then the cells are left for 5 min. in the incubator at 37 ° C and 5% C0 2 incubated.
- the cells are taken up in the modified RPMI medium (see above) and the number of cells determined.
- the cells are stained with trypan blue and counted in a Neubauer chamber.
- the cells are seeded again in the modified RPMI medium (see above) in a defined cell number of 80,000 cells per well (6-well Clear Plate, TCT, PS (Nunc)). The mixture is then incubated for 24 h at 37 ° C and 5% CO 2, then the medium removed. Subsequently, 1980 ⁇ of the substance dilution are abandoned. For this dilution of the substance, Eugenia uniflora extract is dissolved in DMSO and then filtered through a sterile filter (0.2 ⁇ m, Millipore, article no. SLLG013SL). Then the solution with the
- modified RPMI medium in this case, the FBS content in the RPMI medium is only 5%
- concentration of the extract is 0.1 mg / ml.
- the medium is aspirated and the cells are washed with 1000 ⁇ DPBS (Invitrogen, Article No. 14190). It is again aspirated 250 ⁇ l of HyQtase-Cell Detachment Solution (Hyclone, article No. SV30030.01) are added to the cells. The 6-well plate is pivoted several times and the HyQtase- Cell Detachment Solution is then removed by suction. Then the cells are left for 5 min. incubated in incubator at 37 ° C and 5% CO 2 . The cells are then taken up in 1.5 ml of DPBS (Invitrogen, Item No. 14190) and transferred to Cup (SARSTEDT, Ref. 72.692.005).
- DPBS Invitrogen, Article No. 14190
- the melanin content is lowered in the melanocytes by an Eugenia uniflora water extract.
- DMSO (0.1%) + a-MSH may also be used during treatment
- Phototherapy can be formed in the skin and corresponds to one
- DMSO 0.15% corresponds to the normally pigmented neonatal skin without light stimulation.
- the transmittance of 466 nm wavelength light is measured to determine the efficiency of phototherapy in neonatal jaundice.
- samples A are transferred to a cuvette and the transmission is determined at 466 nm.
- the electroluminescent device of Example 1 is used for irradiating the samples. Analogous results can also be achieved with other light sources (eg PLED, OLED).
- the sample corresponding to the untreated, unirradiated neonatal skin (DMSO (0.1%) was set to 100%, resulting in the following transmission values:
- compositions of skin lightening compounds are provided.
- the emulsions can be prepared under mild conditions at room temperature. By increasing the content of ascorbic acid, 2- (4-dihexylylamino-2-hydroxy-benzoyl) benzoic acid (R) -2 - ((R) -3,4-dihydroxy-5-oxo-2,5-dihydroxy) furan-2-yl) -2-hydroxyethyl ester. Ideally, the production is carried out under inertization (exclusion of oxygen).
- composition of skin lightening compound with additional active ingredient is provided.
- RonaCare Tiliroside 1 0.5 0.3 0.1 0.05
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Abstract
L'invention concerne, entre autres, des inhibiteurs de synthèse de la mélanine servant au traitement de maladies de la peau, la peau étant irradiée en outre au moyen d'une source de rayonnement artificielle. L'invention concerne en outre des traitements cosmétiques.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE102011117364A DE102011117364A1 (de) | 2011-10-29 | 2011-10-29 | Hautaufheller in der Phototherapie |
PCT/EP2012/004019 WO2013060407A1 (fr) | 2011-10-29 | 2012-09-26 | Agent éclaircissant de la peau en photothérapie |
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Publication Number | Publication Date |
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EP2771032A1 true EP2771032A1 (fr) | 2014-09-03 |
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Application Number | Title | Priority Date | Filing Date |
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EP12773216.2A Withdrawn EP2771032A1 (fr) | 2011-10-29 | 2012-09-26 | Agent éclaircissant de la peau en photothérapie |
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US (2) | US20140323950A1 (fr) |
EP (1) | EP2771032A1 (fr) |
JP (1) | JP6151262B2 (fr) |
DE (1) | DE102011117364A1 (fr) |
WO (1) | WO2013060407A1 (fr) |
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DE102011102824A1 (de) * | 2011-05-30 | 2012-12-06 | Merck Patent Gmbh | Extrakte aus Eugenia uniflora |
CN105451815A (zh) * | 2013-08-22 | 2016-03-30 | 默克专利有限公司 | 光疗法中的漫射颜料 |
DE102014102114A1 (de) * | 2014-02-19 | 2015-08-20 | Christiane Hauck | Kosmetische oder pharmazeutische Zubereitungen zur Prävention und Behandlung der Cellulite |
CN103784570B (zh) * | 2014-03-05 | 2016-05-25 | 张丽 | 一种治疗新生儿黄疸的中药制剂 |
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Also Published As
Publication number | Publication date |
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JP6151262B2 (ja) | 2017-06-21 |
JP2014532672A (ja) | 2014-12-08 |
US20160339263A1 (en) | 2016-11-24 |
WO2013060407A1 (fr) | 2013-05-02 |
US20140323950A1 (en) | 2014-10-30 |
DE102011117364A1 (de) | 2013-05-02 |
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