WO1995001157A1 - Utilisation d'oximes hydroxyphenyliques comme agents photoprotecteurs chelatants - Google Patents

Utilisation d'oximes hydroxyphenyliques comme agents photoprotecteurs chelatants Download PDF

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Publication number
WO1995001157A1
WO1995001157A1 PCT/US1994/007202 US9407202W WO9501157A1 WO 1995001157 A1 WO1995001157 A1 WO 1995001157A1 US 9407202 W US9407202 W US 9407202W WO 9501157 A1 WO9501157 A1 WO 9501157A1
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composition
hydroxy
skin
hydrogen
alkyl
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PCT/US1994/007202
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English (en)
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Rodney Dean Bush
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The Procter & Gamble Company
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Publication of WO1995001157A1 publication Critical patent/WO1995001157A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/51—Chelating agents

Definitions

  • TECHNICAL FIELD This invention relates to topical compositions useful for protecting the skin from the harmful effects of ultraviolet irradiation, such as sunburn and sun-induced premature aging of the skin.
  • the major short term hazard of prolonged exposure to sunlight is erythema (i.e., sunburn).
  • the 290 to 320 nanometer wavelength ultraviolet radiation range designated as the "UVB” wavelength range, tends to be the primary cause of erythema.
  • the 320 to 400 nanometer wavelength ultra ⁇ violet radiation range designated as the "UVA” wavelength range, also produces erythema.
  • UVB nanometer wavelength ultraviolet radiation range
  • UVA ultra ⁇ violet radiation range
  • This condition is characterized by wrinkling and yellowing of the skin, along with other physical changes such as cracking, telangiectasis (spider vessels), solar keratoses (growths), ecchymoses (subcutaneous hemorrhagic lesions), and loss of elasticity (sagging).
  • the adverse effects associated with exposure to UVA and UVB wavelength radiation are more fully discussed in DeSimone, "Sunscreen and Suntan Products", Handbook of Nonprescription Drugs. 7th Ed, Chapter 26, pp. 499-5 1 (American Pharmaceutical Association, Washington, D.C.; 1982); Grove and Forbes, "A Method for Evaluating the Photoprotection Action of Sunscreen Agents against UV-A Radiation", International Journal of Cosmetic Science. 4, pp.
  • Sunblock agents are commercially available to protect the skin from UV radiation. These agents scatter or reflect ultraviolet radiation. Examples include titanium dioxide and zinc oxide. However, these agents are very susceptible to rub-off or wear-off, resulting in little or no protection.
  • the most common agents for sun protection are sunscreens. These agents exert their effects through absorption of ultraviolet radiation so that it cannot penetrate the skin. Sunscreens must remain on the surface of the skin during exposure. However, sunscreens are easily rubbed off or washed off by sweating or swimming and can also be lost by penetration into the skin.
  • the subject invention relates to methods and photoprotective compositions comprising: (a) from about 0.1% to about 2% of a compound having the structure:
  • R, R', R", R"', and R" are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkoxy, and amide; and (b) a pharmaceutically-acceptable topical carrier.
  • alkyl means carbon-containing chains which may be straight, branched or cyclic; substituted or unsubstituted; saturated, monounsaturated (i.e., one double or triple bond in the carbon chain), or polyunsaturated (i.e., two or more double bonds in the carbon chain, two or more triple bonds in the carbon chain, one or more double and one or more triple bonds in the carbon chain).
  • alkyl are preferably as follows: preferred alkyl are straight or branched chain, more preferably branched chain.
  • Preferred alkyl are mono-, di-, or trisubstituted, or unsubstituted, more preferably monosubstituted or unsubstituted.
  • Preferred alkyl are saturated or unsaturated, preferably saturated; if unsaturated, preferably there is from one to three unsaturations; more preferably, one or two unsaturations; still more preferably, one unsaturation.
  • Preferred alkyl are C1-C18 a
  • alkoxy means an — O-alkyl moiety.
  • carboxy and carboxy acid mean a -COOH moiety.
  • Carboxy ester as used herein, means a -COO-alkyl moiety.
  • aryl means substituted or unsubstituted phenyl. Preferred substituents include alkyl, halogen, and hydroxy.
  • substituted in reference to alkyl groups, means such groups that can be mono- or polysubstituted.
  • D refers to an alkyl group. Preferred substituents are selected from halogen, hydroxy, alkoxy, carboxy, carboxy esters, oxo, thiol, alkylthio (D-S-), alkyldithio (D-S-S-), amino, alkylamino, dialkylamino, amide, alkylamide, dialkylamide, and alkylsilyl (D-Me2Si-).
  • safe and photoprotectively effective amount means an amount sufficient to substantially reduce the deleterious effects of ultraviolet radiation to skin but not so much as to cause serious side effects or adverse skin reactions.
  • regulating means preventing, retarding, or arresting. As used herein, all percentages are by weight unless otherwise specified.
  • active compounds having the following structure:
  • R, R', R", R"', and R" are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkoxy, and amide.
  • Preferred active compounds have a total of twenty two carbon atoms or fewer and have a molecular weight of less than one thousand. Heavier and larger active compounds often will not usually penetrate the skin as well as is desired for good efficacy.
  • R, R', R", R" ⁇ and R"" are hydrogen or alkyl. If R, R', R", R"', or R"" is alkyl, preferred alkyl are C-
  • the alkyl can be branched or straight chain, preferably branched; preferred is branched wherever feasible to render the molecule more compact.
  • the alkyl may be saturated or unsaturated, preferably saturated; if unsaturated, preferably there is from one to three unsaturations; more preferably, one or two unsaturations; still more preferably, one unsaturation.
  • Preferred alkyl are unsubstituted.
  • Also preferred alkyl are methyl and ethyl.
  • at least one of R, R', R", R'", and R"" is alkyl; more preferably, two are alkyl; still more preferably, three are alkyl, more preferably still, four are alkyl.
  • R is alkyl.
  • R, R', R", R"', or R" is substituted alkyl
  • preferred substitutents include hydroxy, alkoxy, carboxy, carboxy ester, halo, oxo, amino, akylamino, dialkylamino, amide, alkylamide, and dialkylamide. More preferred substituents are selected from hydroxy, alkoxy, oxo, halo, carboxy esters and dialkylamino; more preferably selected from hydroxy, alkoxy, and halo.
  • Alkyl or substituted alkyl R', R", R'", or R"" may form a cyclic or hetorocyclic ring with the adjacent R", R' or R" ⁇ R" or R"", or R"' group respectively.
  • R, R', R", R'", or R" is cyclic alkyl, preferably it is C3-C8 cyclic alkyl; preferably it is saturated; more preferably it is cyclopropyl. Preferably no more than two of R', R", R'", and R"" are cyclic alkyl; if R ⁇ R", R'", or R"" is cyclic alkyl, preferably it is R' and/or R'". If R is cyclic alkyl, preferably it is selected from cyclopropyl, cyclopentyl, and cyclohexyl.
  • R, R', R", R'", or R"" or a substituent thereof is halogen, preferably it is iodine; more preferably bromine; more preferably still, chlorine; still more preferably, fluorine.
  • R, R', R", R" ⁇ or R"" or a substituent thereof is alkoxy, preferably the alkyl moiety of the alkoxy is C ⁇
  • R', R", R" ⁇ or R"" is hydroxy, preferably not all are hydroxy; more preferably, only one is hydroxy; preferably it is R'.
  • R', R", R"', or R" has a carboxy acid or carboxy ester substituent, preferably not all of R', R", R"', or R"" have a carboxy acid or carboxy ester substituent; more preferably, only one has a carboxy acid or carboxy ester substituent; preferably the one is R' or R".
  • R"" preferably does not have a carboxy acid or carboxy ester substituent. If R', or R" has a carboxy acid or carboxy ester substituent, preferably the substituent is carboxy acid. If R'" or R"" has a carboxy acid or carboxy ester substituent, preferably the substituent is a carboxy ester. If R has a carboxy acid or carboxy ester substituent, preferably the substituent is a carboxy ester rather than a carboxy acid.
  • R', R", R'", or R" has an oxo substituent, preferably not all of R', R", R'", or R"" have an oxo substituent; more preferably, only one has an oxo substituent; preferably the one is R' or R". If R has an oxo substituent, for stability reasons, the carbonyl carbon ⁇ i.e. the oxo-substituted carbon) should not be two positions from the oxime carbon ⁇ i.e. at the 3-position if the oxime carbon is in the 1 -position.)
  • R', R", R" ⁇ or R" are selected from hydrogen, hydroxy, methyl, methoxy, ethyl, ethoxy, isopropyl, t-butyl, ethoxyethyl (-CH2CH2OCH2CH3), hydroxyethyl (-CH 2 CH 2 OH), and trifluoromethyl (-CF3).
  • R or substituent thereof reactive with the oxime moiety should be 6 or 5 positions from the oxime oxygen or nitrogen atoms.
  • Such reactive substituents include halides, oxo, carboxy, and hydroxy.
  • Preferred R are selected from hydrogen, hydroxy, methyl, and ethyl, isopropyl, t-butyl, ethoxymethyl (-CH2OCH2CH3), 1-dimethylamino-1- pentanoyl (-CH 2 CH2CH 2 CH2C(O)N(CH3)2), 4-oxopentyl
  • Preferred active compounds of the subject invention include salicylaldoxime:
  • the active compounds useful in the subject invention are generally moderate UV-light absorbers, but provide surprisingly high values in an SPF test (based on the Test Method described hereinbelow).
  • the active compounds are also good metal chelators and provide protection against chronic skin aging and wrinkling due to metal catalyzed free radical formation, which may be caused by skin exposure to UV-light or other causes. Therefore, the compositions of the subject invention which comprise the active compounds can provide excellent protection against both short term (acute) and long term (chronic) exposure to UV-light and against damage due to other causes of metal-catalyzed free radical formation.
  • Active compounds useful in the subject invention also include metal complexes of the compounds of the subject invention which do not participate in free radical reactions.
  • the active compounds of the subject invention are metal chelators and readily form complexes with metal ions.
  • the inclusion of metal complexed active compounds in the compositions of the subject invention can enhance the acute photoprotection provided by the composition.
  • a metal ion generally complexes with from about 1 to about 3 molecules of a active compound of the subject invention.
  • each mole of metal ion is substantially complexed, i.e., is complexed with a number of moles of active compound equal to the metal ion's valence number plus or minus one, more preferably each mole of metal ion is fully complexed, i.e., is complexed with a number of moles of active compound molecules equal to the metal ion's valence number.
  • Preferred metal ions for inclusion in the metal complexed active compounds useful in the subject invention include sodium, aluminum, zinc, lithium, magnesium, potassium, calcium, rubidium, strontium, titanium, zirconium, vanadium, chromium, manganese, cobalt, copper, gallium, scandium, silicon, boron, praseodymium, lanthanum, promethium, samarium, and europium; more preferred metal ions are those which do not have d-electrons: sodium, aluminum, zinc, lithium, magnesium, potassium, calcium and scandium; most preferred metal ions are sodium, aluminum, zinc, lithium, gallium and scandium.
  • Salicylhydroxamic acid is obtained from Aldrich Chemical Co.
  • EXAMPLE 2 The following compound is prepared by the reaction of hydroxylamine with the corresponding ketone obtained commercially from Aldrich Chemical Company, 1001 West Saint Paul Avenue, Milwaukee, Wl 53233.
  • compositions of the subject invention comprise a safe and effective amount of an active compound useful in the subject invention, disclosed hereinabove, preferably from about 0.01 % to about 2%, more preferably from about 0.1% to about 1.5%, more preferably still from about 0.5% to about 1%.
  • the ability of the active compounds to act as sunscreens by absorbing ultraviolet light is poor due to the low concentration of the active compounds.
  • the subject compositions are preferably formulated such that the active compounds penetrate into the skin; this provides optimum photoprotection from the compositions.
  • sunscreen compounds provide optimum photoprotection when they remain on the skin surface and do not penetrate the skin, skin penetration by the subject active compounds is achieved by preferably formulating compositions with active compounds having low molecular weight, preferably below 1000, more preferably below 500; by preferably formulating compositions with active compounds having a neutral charge in the composition; and by preferably formulating compositions with ingredients which enhance skin penetration of the active compounds.
  • compositions of the subject invention comprise a topical pharmaceutically-acceptable or cosmetically- acceptable carrier.
  • pharmaceutically-acceptable carrier and “cosmetically-acceptable”, as used herein, mean one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or lower animal.
  • Such carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or lower animal being treated.
  • Such carrier preferably comprises from about 98% to about 99.99%, more preferably from about 98.5% to about 99.9%, more preferably still from about 99% to about 99.5% of the composition.
  • Topical Carriers The topical compositions of the subject invention may be made into a wide variety of product types. These include, for example, lotions, creams, beach oils, gels, sticks, sprays, ointments, pastes, mousses and cosmetics. These product types may comprise either of two basic types of carrier systems, solutions and emulsions.
  • the topical compositions of the subject invention formulated as solutions typically include a pharmaceutically-acceptable aqueous or organic solvent.
  • Preferred solvents in addition to being capable of having dispersed or dissolved therein the active compound, also possesses acceptable safety (e.g., irritation and sensitization characteristics), as well as good aesthetic properties (e.g., does not feel greasy or tacky). Water is a typical aqueous solvent.
  • suitable organic solvents include: propylene glycol, polyethylene glycol (200-600), polypropylene glycol (425-2025), glycerol, 1,2,4-butanetriol, sorbitol esters, 1 ,2,6-hexanetriol, ethanol, isopropanol, butanediol, and mixtures thereof.
  • Preferred solutions of the subject invention comprise from about 0.01 % to about 2%, more preferably from about 0.1 % to about 1.5%, more preferably from about 0.5% to about 1% of the active compound, and from about 98% to about 99.99%, more preferably from about 98.5% to about 99.9%, more preferably from about 99% to about 99.5% of an • acceptable organic solvent.
  • a propellant is added to a solution composition.
  • propellants useful herein include, but are not limited to, the chlorinated, fluorinated and chloro-fluorinated lower molecular weight hydrocarbons. A more complete disclosure of propellants useful herein can be found in Sagarin, Cosmetics Science and Technology, 2nd Edition, Vol. 2, pp. 443-465 (1972), incorporated herein by reference.
  • Topical compositions of the subject invention may be formulated as a solution comprising an emollient.
  • An example of a composition formulated in this way would be a beach oil product.
  • Such compositions typically comprise from about 0.01% to about 2%, preferably from about 0.1% to about 1.5%, more preferably from about 0.5% to about 1% of the active compound and from about 1% to about 50%, preferably from about 5% to about 20% of a topical pharmaceutically-acceptable emollient.
  • emollients refer to materials used for the prevention or relief of dryness, as well as for the protection of the skin. A wide variety of suitable emollients are known and may be used herein. Sagarin, Cosmetics.
  • a lotion can be made from a solution carrier system.
  • Lotions typically comprise from about 0.1% to about 2%, preferably from about 0.5% to about 1.5%, of the active compound; from about 1% to about 20%, preferably from about 5% to about 10%, of an emollient; and from about 50% to about 90%, preferably from about 60% to about 80%, water.
  • a cream of the subject invention would comprise from about 0.1% to about 2%, preferably from about 0.5% to about 1.5%, of the active compound; from about 5% to about 50%, preferably from about 10% to about 20%, of an emollient, and from about 45% to about 85%, preferably from about 50% to about 75%, water.
  • An ointment may comprise a simple base of animal or vegetable oils or semi-solid hydrocarbons (oleaginous). Ointments may also comprise abso ⁇ tion ointment bases which absorb water to form emulsions. Ointment carriers may also be water soluble. An ointment may also comprise from about 2% to about 10% of an emollient plus from about 0.1% to about 2% of a thickening agent. A more complete disclosure of thickening agents useful herein can be found in Sagarin, Cosmetics. Science and Technology, 2nd Edition, Vol. 1, pp. 72-73 (1972), incorporated herein by reference.
  • the carrier is formulated as an emulsion, from about 1% to about 10%, preferably from about 2% to about 5%, of the carrier system comprises an emulsifier.
  • Emulsifiers may be nonionic, anionic or cationic.
  • Lotions and creams can be formulated as emulsions as well as solutions.
  • lotions comprise from about 0.1% to about 2%, preferably from about 0.5% to about 1.5%, of the active compound; from about 1% to about 20%, preferably from about 5% to about 10%, of an emollient; from about 25% to about 75%, preferably from about 45% to about 95%, water; and from about 0.1% to about 10%, preferably from about 0.5% to about 5%, of an emulsifier.
  • Such creams would typically comprise from about 0.1 % to about 2%, preferably from about 0.5% to about 1.5%7of the active compound; from about 1% to about 20%, preferably from about 5% to about 10%, of an emollient; from about 20% to about 80%, preferably from about 30% to about 70%, water; and from about 1% to about 10%, preferably from about 2% to about 5%, of an emulsifier.
  • topical compositions of the subject invention are formulated as a gel or a cosmetic stick, a suitable amount of a thickening agent is added to a cream or lotion formulation.
  • compositions of the subject invention may also be formulated as makeup products such as foundations, or lipsticks.
  • topical compositions of the subject invention may comprise, in addition to the aforementioned components, a wide variety of additional oil-soluble materials and/or water-soluble materials conventionally used in topical compositions, at their art-established levels.
  • compositions of this invention may also be subject in the compositions of this invention. These include humectants, proteins and poly- peptides, preservatives and an alkaline agent.
  • topical compositions herein can contain conventional cosmetic adjuvants, such as dyes, opacifiers (e.g., titanium dioxide), pigments and perfumes.
  • compositions of the subject invention can be tested using either of the following test methods to determine effective dosage levels of the active compound.
  • the guinea pig is used as a model for determination of sun protection factor (SPF) values of topical protective agents; see, e.g., Leroy, D. & P.
  • SPF sun protection factor
  • Animals - Male Hartley strain guinea pigs are obtained from Charles River Laboratories, Portage, Ml. The guinea pigs weigh approximately 300 g at the start of experimental work. All animals are housed in indivudual cages in a room with controlled temperature and humidity and with a 12-hour light/darkness cycle. They are given a standard Purina Chow diet and water ad libitum.
  • UV Radiation Source and Radiometer - A model 81172 Oriel Co ⁇ . (Stratford, CT) solar simulator equipped with a 1000-watt zenon arc ozone-free lamp is used. Schott Glass Technologies, Inc. (Duryea, PA) filters (a 3-mm WG-305 (to remove UVC) and a 1-mm UG-5 filter (to remove visible light)) are inserted in the light path just past the simulator output port to simulate the solar UV spectrum. Total UVB or UVA output is determined with an Interna- tional Light (Newburyport, MA) model IL1350 radiometer equipped with SED 240 (UVB) and SED 015 (UVA) sensors.
  • UVB Interna- tional Light
  • Spectral scans are recorded on a model 4950 strip chart recorder (Bausch & Lomb, Austin, TX) using an International Light double monochrometer spectro-radiometer system (model IL 700A/760/791).
  • Guinea Pig SPF Measurements The dorsal skin of guinea pigs is shaved with electric clippers and then depilated with Neet® Lotion Hair Remover (Whitehall Laboratories, New York, NY). The skin is rinsed under warm tap water and dried with a towel. Sixteen hours later, the dorsal skin is treated with 2 mg/cm 2 of test material solution.
  • the adhesive side of the tape covering the dorsal skin area is coated with black construction paper to prevent reddening of the skin from adherence of the tape to that skin region.
  • the time between topical treatment and irradiation with UV-light is approximately 15 minutes.
  • Test Method II - Ornithine Decarboxylase Assay Scope This method describes an assay procedure for the determination of the enzyme ornithine decarboxylase (ODC) in mouse skin epidermis.
  • the assay is linear up to at least 40 minutes of incubation of enzyme with substrate, with a deviation between replicates of less than 10%.
  • the method is based on published procedures for determination of mouse epidermal ODC. (See Lowe, N., A.K. Verma, and R.K. Boutwell, Journal of Investioational Dermatology. Vol. 71 (1978), pp. 417-418; Verma, A.K., N.J. Lowe & R.K. Boutwell, Cancer Research, Vol.
  • Tissue homogenizer - Tissuemizer (type SDT-1810, Tekrnar, Co., Cincinnati, OH)
  • Homogenization buffer 50 mM sodium phosphate, 1.25 mM EDTA, 2.5 mM DTT and 0.1 mM PLP [pH 7.1].
  • Substrate solution 1.6 mM L-ornithine, 0.65 mM PLP, 20 micro Ci/ml L-[ 14 C]-ornithine.
  • Citric acid solution Dissolve 384 g of citric acid in 600 ml of water; bring the volume up to 1000 ml: 2M citric acid (pH 1.5). This is prepared in advance and kept frozen at -20°C in 50-ml aiiquats in 50 ml polypropylene centrifuge tubes until needed. Then it is thawed, and kept at room temperature.
  • Dye Reagent Dilute 1 volume of Dye Reagent Concentrate with 4 volumes of distilled-deionized water. Filter through Whatman No. 1 filter paper and store dilute reagent in a glass container at room temperature. Prepare just before use. 5. Protein standard: The Bio-Rad Protein Standard supplied in the kit is lyophilized bovine protein sealed under nitrogen. To reconstitute, add
  • Test material solutions are applied topically to the dorsal skin of the mouse.
  • a control group of mice receives topical application of the same vehicle as is in the test material solution (without the active compound).
  • Test material solution or control vehicle is applied to the skin of each mouse at an application rate of approximately 2 ml/cm 2 .
  • Topical treatments are done three times: AM and PM of Day 1 and AM of Day 2.
  • mice Two hours after the third treatment, the dorsal skin of the mice is exposed to 2X MED (minimum erythemal dose) with a 1000-watt Xenon arc solar simulator. The total UV dose is approximately 1.6 J/cm 2 . Twenty-four hours after irradiation, mice are sacrificed by cervical dislocation, and the dorsal skin is removed. Procedure: 1. Whole dorsal skin from a mouse is placed dermis side down on an ice cold glass plate. The epidermal side of the skin is scraped with a razor blade 20 times to remove the epidermis, which adheres to the razor blade.
  • 2X MED minimum erythemal dose
  • Epidermal shave scrapings are transferred to individual 12 X 75 mm clear polystyrene tubes containing 0.6 ml of ice cold homogenization buffer.
  • tissue is homogenized on ice for 20 seconds at a homogenizer power control setting of 80 (0-100 scale).
  • the homogenate is transferred to a 1.5 ml polypropylene micro test tube and centrifuged at 16,000 x g for 10 minutes at 4°C in an Eppendorf centrifuge. 5.
  • the clear supernatant solution is transferred with a Pasteur pipette to a 1.2 cc cryogenic vial.
  • Add 0.1 ml of supernatant solution to a 15 x 85 mm glass test tube and place in a 37°C shaking water bath for 5 minutes. Duplicate assays are run for each sample. Six blank assays containing 0.1 ml of homogenization buffer are also run.
  • the assay is started by addition of 0.025 ml of de-gassed substrate solution. This gives a final concentration of assay components of 40 mM sodium phosphate, 1 mM EDTA, 2 mM DTT, 0.2 mM PLP, 0.4 mM ornithine, and 0.5 micro Ci of 14 C-ornithine.
  • the assay tube is immediately sealed with a rubber stopper and center well assembly, the center well containing 0.1 ml of methylbenzethonium hydroxide.
  • the reaction is run at 37°C in a shaker water bath at 50 rpm for 30 minutes.
  • the assay is stopped by piercing the rubber stopper and injecting 0.25 ml of 2M citric acid solution into the assay solution. Particular care is taken not to inject citric acid into the center well assembly.
  • the assay mixture is kept at room temperature for 30 minutes after citric acid injection to ensure complete absorption of 14 CO2 by methylbenzethonium hydroxide contained in the center well.
  • the center well bucket is transferred, by cutting with scissors the center well stem, to scintillation vials containing 10 ml of scintillation fluid and shaken thoroughly.
  • Standards are prepared by adding 0.025 ml of substrate solution to 10 ml of scintillation fluid; this amount of
  • 1 C represents total conversion of substrate to CO2 in the assay.
  • the Ornithine Decarboxylase (ODC) value (pmole/hr mg) for the test compound is compared to the ODC value (pmole/hr mg) for the control to give a percent difference between the two values.
  • ODC Ornithine Decarboxylase
  • Preferred active compounds useful in the subject invention demonstrate at least a 20% decrease, preferably at least a 50% decrease, in the ODC value as compared to the ODC value of the control.
  • compositions of the subject invention can comprise other photoprotectively active compounds such as sunscreens, sunblocks, anti-inflammatories, antioxidants or radical scavengers.
  • sunscreens sunblocks
  • anti-inflammatories antioxidants
  • radical scavengers radical scavengers
  • Combination Actives A. Sunscreens and Sunblocks Optimum protection against sun damage can be obtained by using a combination of the active compounds of the subject invention together with sunscreens or sunblocks.
  • Useful sunblocks include, for example, zinc oxide and titanium dioxide.
  • compositions of the subject invention may include sunscreens in compositions of the subject invention at low levels. The inclusion of sunscreens in compositions of the subject invention at low levels will not significantly reduce the tanning response of the user but will enhance immediate protection against acute UV damage.
  • sunscreening agents are suitable for use in combination with the active compounds.
  • sunscreening agents include, for example: p-Aminobenzoic acid, its salts and its derivatives (ethyl, isobutyl, glyceryl esters; p-dimethylaminobenzoic acid); Anthranilates (i.e., o-aminobenzoates; methyl, menthyl, phenyl, benzyl, phenylethyl, linalyl, terpinyl, and cyclohexenyl esters); Salicylates (amyl, phenyl, benzyl, octyl, menthyl, glyceryl, and dipro- pyleneglycol esters); Cinnamic acid derivatives (menthyl and benzyl esters, a-phenyl cinnamonitrile; butyl cinnamoyl pyruvate); Dihydroxycinnamic acid derivatives (umbelliferone, methylumbelliferone, methylacet
  • 2-ethylhexyl-2-cyano-3,3-diphenylacrylate 2-ethylhexylsalicylate, glyceryl p-aminobenzoate, 3,3,5-trimethylcyclohexylsalicylate, methylanthranilate, p- -dimethyl-aminobenzoic acid or aminobenzoate, 2-ethylhexyl-p- -dimethylamino-benzoate, 2-phenylbenzimidazole-5-sulfonic acid,
  • sunscreens useful in the compositions of the subject invention are 2-ethylhexyl-p-methoxycinnamate, butyl- methoxydibenzoylmethane, 2-hydroxy-4-methoxybenzophenone, octyl- dimethyl p-aminobenzoic acid and mixtures thereof.
  • a safe and photoprotectively effective amount of sunscreen may be used in the compositions of the subject invention.
  • the sunscreening agent must be compatible with the active compound.
  • the composition may comprise from about 1% to about 20%, preferably from about 2% to about 10%, of a sunscreening agent. Exact amounts will vary depending upon the sunscreen chosen and the desired Sun Protection Factor (SPF). Because of the photoprotecting capability of the active compound against erythema, the combination provides an SPF greater than that of the sunscreen alone.
  • sunscreens such as those disclosed in U.S. Patent No. 4,937,370 issued to Sabatelli on June 26, 1990, and in U.S. Patent No. 4,999,186 issued to Sabatelli and Spirnak on March 12, 1991 , both incorporated herein by reference.
  • the sunscreening agents disclosed therein have, in a single molecule, two distinct chromophore moieties which exhibit different ultra-violet radiation absorption spectra.
  • One of the chromophore moieties absorbs predominantly in the UVB radiation range and the other absorbs strongly in the UVA radiation range.
  • the compositions of the subject invention, with or without sunscreens may also be formulated as shampoos, conditioners, mousses or other hair care products. It is known that UV radiation damages hair and the photoprotecting agents of the subject invention may minimize such damage. Furthermore such formulations will provide a means for applying the photoprotecting agents of the subject invention onto the scalp, which is also susceptible to UV damage.
  • any compatible art-recognized hair care formulations can be used with the active compound added at a level of from about 1% to about 5%. If desired, a sunscreen may also be included at from about 1% to about 5%.
  • An agent may also be added to any of the compositions of the subject invention to improve the skin substantivity of those compositions, particularly to enhance their resistance to being washed off by water, or rubbed off.
  • a preferred agent which will provide this benefit is a copolymer of ethylene and acrylic acid. Compositions comprising this copolymer are disclosed in U.S. Patent 4,663,157, Brock, issued May 5, 1987, which is incorporated herein by reference.
  • an anti-inflammatory agent is included as an active along with the active compound.
  • the anti-inflammatory agent protects strongly in the UVA radiation range (though it also provides some UVB protection as well).
  • the topical use of anti-inflammatory agents reduces photo-aging of the skin resulting from chronic exposure to UV radiation.
  • a safe and effective amount of an anti-inflammatory agent may be added to the compositions of the subject invention, generally from about 0.1% to about 10%, preferably from about 0.5% to about 5%, of the composition.
  • the exact amount of anti-inflammatory agent to be used in the compositions will depend on the particular anti-inflammatory agent utilized since such agents vary widely in potency.
  • a preferred composition of the subject invention comprises an active compound, a sunscreen, and an anti-inflammatory agent together for photoprotection in the amounts disclosed for each individually hereinabove.
  • the subject invention further relates to a method for protecting the skin of humans and lower animals from the deleterious effects of radiation, particularly UV radiation, and/or other causes of metal-catalyzed free radical production in the skin tissue.
  • Such protection by the active compound extends to damage resulting from acute UV exposure, e.g. erythema. It also extends to protection from damage resulting from chronic UV exposure, e.g. photoaging.
  • Such protection also extends to damage resulting from sources of radiation other than the sun; non-limiting examples include ultraviolet lights (e.g., tanning lights), x-rays, lasers, etc.
  • Such a method comprises applying to the skin of the human or lower animal a safe and effective amount of the active compounds disclosed hereinabove to be useful in the subject invention. This may be accomplished by using a composition comprising the active compound as disclosed hereinabove.
  • the active compounds involved in each of the following methods may be simply spread over the skin, or rubbed into the skin to enhance penetration of the active compound.
  • the active compounds are preferably applied in conjunction with UV exposure, i.e., prior to, during, or after UV exposure. More specifically, the active compounds are preferably applied from several hours, preferably up to 4 hours, prior to UV exposure, to up to 30 minutes after UV exposure, or anytime in between.
  • topical application of the active compounds prior to exposure of the skin to UV radiation is preferred.
  • topical application of the active compounds is preferably done on a chronic basis.
  • the active compounds are preferably topically applied to the skin about daily, preferably prior to substantial exposure of the skin to UV radiation.
  • Such application preferably occurs from at least about once to about 5 times daily, more preferably about 2 times daily, but for particularly effective compositions preferably once daily.
  • Such application preferably occurs over long periods of time, preferably for more than one month, more preferably for more than six months, more preferably still for more than one year, 5 years, 10 years or more.
  • a safe and photoprotectively effective amount of an active compound is from about 0.001 mg to about 1.0 mg, preferably from about 0.01 mg to about 0.5 mg, more preferably from about 0.05 mg to about 0.1 mg of the active compound per cm 2 skin.
  • a preferred method of the subject invention for preventing deleterious effects caused by UV exposure involves applying both a safe and photoprotectively effective amount of an active compound and a safe and photoprotectively effective amount of one or more of an additional sun ⁇ screening agent, and/or an anti-inflammatory agent, to the skin simul ⁇ taneously.
  • an additional sun ⁇ screening agent and/or an anti-inflammatory agent
  • skin simul ⁇ taneously is meant applying the agents to the skin at the same situs on the body at about the same time. Though this can be accomplished by applying the agents separately to the skin, preferably a composition comprising all the desired agents commingled is applied to the skin.
  • the amount of sunscreening agent applied is generally from about 0.01 mg to about 1.0 mg. preferably from about 0.05 mg to about 0.5 mg, per cm 2 of skin.
  • the amount of anti-inflammatory agent is generally from about 0.005 mg to about 0.5 mg, preferably from about 0.01 mg to about 0.1 mg.
  • Example 10 A moisturizing lotion is prepared by combining the following components utilizing conventional mixing techniques.
  • Component Percent by Weight of Composition Carbomer viscosity control agents 0.23
  • This lotion may be topically applied to inhibit damage caused by radiation, particularly acute or chronic UV exposure.
  • Use of an amount of lotion sufficient to deposit about 0.5 mg/cm 2 of salicylhydroxamic acid to the skin is appropriate.
  • Examples 11 & 12 Skin lotions are prepared by combining the following components utilizing conventional mixing techniques.
  • Carbomer viscosity control agents (commercially 0 0..2233 0.23 available as Acritamer from R.I.T.A. Corp.)
  • lotions are useful for topical application to inhibit damage caused by radiation, particularly acute or chronic UV exposure.
  • Use of an amount of lotion sufficient to deposit about 0.5 mg/cm 2 of o- Hydroxyacetophenone oxime to the skin prior to radiation exposure is appropriate.
  • Suntan creams are prepared by combining the following components utilizing conventional mixing techniques.
  • Component Percent by Weight of Composition
  • creams are useful for topical application to inhibit damage caused by radiation, particularly acute or chronic UV exposure.
  • Example 15 A suntan stick is prepared by combining the following components utilizing conventional mixing techniques.
  • This stick is useful for topical application, for example to the lips, to inhibit damage caused by radiation, particularly acute or chronic UV ex ⁇ posure.
  • a suntan cream is prepared by combining the following components utilizing conventional mixing techniques.
  • This cream is useful for topical application to inhibit damage caused by radiation, particularly acute or chronic UV exposure.
  • Use of an amount of cream sufficient to deposit about 0.2 mg/cm 2 of 1-(2'-hydroxyphenyl)-1- propanone oxime to the skin prior to UV exposure is appropriate.
  • a suntan aqueous face gel is prepared by combining the following components utilizing conventional mixing techniques.
  • This aqueous gel is useful for application to the face to inhibit damage caused by radiation, particularly acute or chronic UV exposure. Use of an amount of gel to deposit about 0.5 mg/cm 2 of salicylhydroxamic acid to the face prior to UV exposure is appropriate.
  • a suntan gel is prepared by combining the following components utilizing conventional mixing techniques.
  • This suntan gel is useful for topical application to inhibit damage caused by radiation, particularly acute or chronic UV exposure.
  • Use of an amount of gel to deposit about 0.5 mg/cm 2 of salicylhydroxamic acid to the skin is appropriate.
  • a suntan oil is prepared by combining the following components utilizing conventional mixing techniques.
  • This suntan oil is useful for topical application to inhibit damage caused by radiation, particularly acute or chronic UV exposure.
  • Use of an amount of oil sufficient to deposit about 0.8 mg/cm 2 of o- hydroxyacetophenone oxime to the skin prior to UV exposure is appropriate.
  • a moisturizing oil-in-water-in-silicone sunscreen emulsion lotion is formed from the following ingredients. Ingredient Percent bv Weight
  • Methylparaben 0.20 Carbomer viscosity control agent (commercially 0.10 available in the Acritamer series from R.I.T.A. Co ⁇ .)
  • Pareth-15-3 polyethylene glycol ester of a 2.00 mixed synthetic C- ⁇ 1-C-15 fatty alcohol, av.3 moles EO
  • the water, pantethine, methylparaben, glycerine and sulfonate emulsifier are heated to about 72-75°C and mixed. Stirring is increased until a vortex forms in the aqueous solution.
  • the thickener, Carbomer is slowly added to the vortex and allowed to mix until completely hydrated and the resultant gel solution is free of gelatinous particles and is uniform in composi- tion.
  • the temperature Is maintained at about 72-75°C with constant agitation.
  • the oil phase ingredients are added to a separate suitably sized vessel and heated to about 80-85°C using slow mechanical stirring once the oil phase becomes molten. At this point the sunscreening agents, naproxen, and 2'-hydroxy-5'-methyl acetophenone oxime are mixed in. When molten, agitation is maintained to keep the oil phase uniform during heating.
  • the heated oil phase is then slowly added to the heated water phase with stirring to form the oil-in-water emulsion.
  • the mechanical stirring means is slowed to avoid unnecessary aeration of the emulsion and mixing is continued for approximately fifteen minutes at 70-75° C.
  • the emulsion is then cooled to about 60 ⁇ C with moderate agitation.
  • the base, triethanolamine is then slowly added to neutralize the acidic Carbomer 940 and the emulsion (pH 6.5) is mixed at moderate speed until uniform.
  • the homogeneous oil-in-water emulsion is then cooled to about 45-50°C and the colorant and odorant oil are added followed by cooling to room temperature (about 25°C) with continued moderate agitation.
  • the four silicone fluids and other silicone phase ingredients are mixed together in a separate vessel until a uniform silicone phase is attained.
  • the oil-in-water emulsion is slowly added to the silicone phase with stirring until a homogeneous oil-in-water-in-silicone double emulsion in lotion form is attained.
  • This moisturizing lotion is useful for topical application to inhibit damage caused by radiation, particularly acute or chronic UV exposure.
  • Use of an amount of lotion sufficient to deposit about 0.5 mg/cm 2 of 2'-hydroxy-5'- methyl acetophenone oxime to the skin is appropriate.
  • This lotion may also be applied several times daily, e.g., 2 or 3 times daily, for extended periods of time, i.e., greater than one week, in amounts sufficient to deposit about 0.5 mg/cm 2 of 2'-hydroxy-5'-methyl acetophenone oxime to the skin to inhibit damage caused by chronic UV exposure.
  • a skin conditioning toilet bar is prepared from the following ingredients.
  • the above composition is prepared in the following manner.
  • the crutcher mix is vacuum dried at ca. 50 mm Hg absolute pressure to reduce the moisture content of the mix to ca. 10% and to plod this soap into noodles. These noodles are passed through a milling step once. Amalgamating Step
  • the once-milled soap noodles are weighed and placed in a batch amalgamator. To about 99.1 parts noodles in the amalgamator are added:
  • a conventional plodder is set up with the barrel temperature at about
  • the plodder used is a dual stage twin screw plodder that allows for a vacuum of about 40 to 65 mm Hg between the two stages.
  • the soap log extruded from the plodder is typically round or oblong in cross-section, and is cut into individual plugs. These plugs are then stamped on a conventional soap stamping apparatus to yield the finished toilet soap bar.
  • the use of this toilet bar for cleansing provides a useful means for deposition of 1-(2'-hydroxyphenyl)-1 -propanone oxime to the skin to inhibit damage caused by radiation, particularly acute or chronic UV exposure. Use of the toilet bar such that about 0.05 mg/cm 2 of 1-(2'-hydroxyphenyl)-1- propanone oxime is deposited on the skin is appropriate.
  • a facial cleanser (lathering mousse composition) is prepared from the following ingredients.
  • Lexein LP170P hydrolyzed animal protein
  • the composition is prepared in a single batch process. DRO water is brought to 71.1°C and the Jaguar polymer is added with agitation. Maintaining agitation, the following ingredients are added sequentially: sodium glycerol ether sulfonate, sodium lauroyl sarcosinate, lauryl alcohol, PEG-600, parabens, EDTA, dye, 2-Hydroxypropylglyceryl ether, stearic acid, aloe vera gel, citric acid and 2'-hydroxy-5'-methyl acetophenone oxime. The mixture is then cooled to 135-140°F and the following ingredients are added sequentially with stirring: Lexein, Germall and perfume. The resulting mixture is cooled to room temperature. Aluminum cans are then filled with the cooled emulsion concentrate.
  • Aerosol activator assemblies are then crimped onto the cans to form a tight seal.
  • Pressurized A-46 Propellant is then pumped into the cans in an amount sufficient to provide a composition consisting of 6% propellant and 94% emulsion concentrate in each can.
  • the composition is dispensed under pressure in the form of a creamy, foaming mousse which can be applied to the skin for cleansing and as a means for deposition of 2'-hydroxy- 5'-methyl acetophenone oxime to the skin to inhibit damage caused by radiation, particularly acute or chronic UV exposure.
  • Use of amount of facial cleanser sufficient to deposit about 0.05 mg/cm 2 of 2'-hydroxy-5'-methyl acetophenone oxime to the skin is appropriate.
  • a cream soap is prepared by combining the following ingredients as described below.
  • the sodium glutamate, sodium hydrogenated tallow glutamate and cocoyl glutamate, polyethylene glycol, polyethylene glycol monostearate, polyoxyethylene sorbitan monostearate, 1-(2'-hydroxyphenyl)-1 -propanone oxime, tocopherol sorbate, flufenamic acid, 2-ethylhexyl methoxycinnamate, and water are dissolved together with heating.
  • the glycerin is added with agitation.
  • the mixture is cooled to about 60°C and the fragrance and preservative are added.
  • the mixture is cooled to 35°C with agitation.
  • the result is a cream soap the use of which for cleansing provides a useful means for deposition of 1-(2'-hydroxyphenyl)-1 -propanone oxime to the skin to inhibit damage caused by radiation, particularly acute or chronic
  • a shampoo composition is made by combining the follow nents.
  • ammonium lauryl sulfate, ammonium laureth sulfate, and ammonium xylene sulfonate are first mixed together.
  • the salicylaldoxime and octyl dimethyl PABA and perfume and minor ingredients are added and the resulting mixture is agitated in a Teckmar® Mill set at 70 for 2 minutes at
  • the resulting shampoo composition is added to hair which has been wetted with water, worked through the hair then rinsed out. This allows for deposition of salicylaldoxime and octyl dimethyl PABA to the scalp to inhibit damage caused by acute or chronic UV exposure. Use of an amount of shampoo sufficient to deposit about 0.05 mg/cm 2 of salicylaldoxime to the scalp is appropriate.
  • Example 25 0.2 mg/cm 2 for Example 25 and 0.07 mg/cm 2 for Example 26 of o- hydroxyacetophenone oxime to the skin inhibits damage caused by radiation, particularly acute or chronic UV exposure.
  • the active is first dissolved in the ethanol.
  • the cremophor is then added, followed by the remaining components.

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Abstract

Procédés et compositions de photoprotection comportant: (a) de 0,1 à 2 % environ d'un composé ayant la structure (I) dans laquelle R, R', R'', R''' et R'''', indépendamment les uns des autres, sont sélectionnés dans le groupe constitué d'hydrogène, halogène, hydroxy, alkyle, alcoxy, et amide; et (b) un excipient topique pharmaceutiquement acceptable.
PCT/US1994/007202 1993-06-29 1994-06-27 Utilisation d'oximes hydroxyphenyliques comme agents photoprotecteurs chelatants WO1995001157A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034228A1 (fr) * 1998-12-04 2000-06-15 Neurosearch A/S Agents de modulation de canaux ioniques
FR2788694A1 (fr) * 1999-01-27 2000-07-28 Oreal Composition pour application topique sur la peau et/ou ses phaneres comprenant au moins un compose comportant un fragment phenyloxime
EP1066821A1 (fr) * 1999-07-08 2001-01-10 Haarmann & Reimer Gmbh Agent cosmétique topique contenant des benzaldoximes
WO2001043712A1 (fr) * 1999-12-14 2001-06-21 Haarmann & Reimer Gmbh Catecholoximes et leur utilisation dans des preparations cosmetiques et dermatologiques
WO2001089468A1 (fr) * 2000-05-24 2001-11-29 Merck Patent Gmbh Utilisation d'aryloximes pour assurer la prophylaxie et/ou le traitement de la formation d'erytheme et/ou de reactions inflammatoires de la peau
WO2001089469A1 (fr) * 2000-05-24 2001-11-29 Merck Patent Gmbh Composition topique comprenant au moins une aryloxime, et son procede de preparation
WO2001089467A1 (fr) * 2000-05-24 2001-11-29 Merck Patent Gmbh Composition contenant au moins un aryloxime et au moins un principe actif pour traiter l'acne et utilisation de ladite composition
WO2003057184A2 (fr) * 2001-12-28 2003-07-17 Integriderm, Inc. Acide hydroxamique et ses derives comme inhibiteurs de la melanocyte tyrosinase pour eclaircissants topiques de la peau
US9663453B2 (en) 2014-10-30 2017-05-30 Universidad De Antofagasta Metabolites and oximes with vasodilator and hypotensive activity
BE1026073B1 (nl) * 2018-03-05 2019-10-07 Purna Pharmaceuticals Nv Verbeterde werkwijze voor het maken van een farmaceutische emulsie

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991016034A1 (fr) * 1990-04-26 1991-10-31 The Procter & Gamble Company Compositions chelatrices comprenant des composes d'oxime
DE4116123A1 (de) * 1991-05-17 1992-11-19 Chem & Pharm Patent Hold Ltd Mittel zur behandlung von hauterkrankungen

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991016034A1 (fr) * 1990-04-26 1991-10-31 The Procter & Gamble Company Compositions chelatrices comprenant des composes d'oxime
DE4116123A1 (de) * 1991-05-17 1992-11-19 Chem & Pharm Patent Hold Ltd Mittel zur behandlung von hauterkrankungen

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034228A1 (fr) * 1998-12-04 2000-06-15 Neurosearch A/S Agents de modulation de canaux ioniques
US6458846B1 (en) 1998-12-04 2002-10-01 Neurosearch A/S Ion channel modulating agents
FR2788694A1 (fr) * 1999-01-27 2000-07-28 Oreal Composition pour application topique sur la peau et/ou ses phaneres comprenant au moins un compose comportant un fragment phenyloxime
EP1023894A1 (fr) * 1999-01-27 2000-08-02 L'oreal Composition cosmétique comprenant au moins un composé comportant un fragment phényloxime
US6228350B1 (en) 1999-01-27 2001-05-08 L'oreal Method of depigmenting and/or bleaching skin and/or body hair or head hair
US6395260B1 (en) 1999-07-08 2002-05-28 Haarmann & Reimer Gmbh Topical cosmetic compositions comprising benzaldoximes
EP1066821A1 (fr) * 1999-07-08 2001-01-10 Haarmann & Reimer Gmbh Agent cosmétique topique contenant des benzaldoximes
WO2001043712A1 (fr) * 1999-12-14 2001-06-21 Haarmann & Reimer Gmbh Catecholoximes et leur utilisation dans des preparations cosmetiques et dermatologiques
WO2001089468A1 (fr) * 2000-05-24 2001-11-29 Merck Patent Gmbh Utilisation d'aryloximes pour assurer la prophylaxie et/ou le traitement de la formation d'erytheme et/ou de reactions inflammatoires de la peau
WO2001089469A1 (fr) * 2000-05-24 2001-11-29 Merck Patent Gmbh Composition topique comprenant au moins une aryloxime, et son procede de preparation
WO2001089467A1 (fr) * 2000-05-24 2001-11-29 Merck Patent Gmbh Composition contenant au moins un aryloxime et au moins un principe actif pour traiter l'acne et utilisation de ladite composition
WO2003057184A2 (fr) * 2001-12-28 2003-07-17 Integriderm, Inc. Acide hydroxamique et ses derives comme inhibiteurs de la melanocyte tyrosinase pour eclaircissants topiques de la peau
WO2003057184A3 (fr) * 2001-12-28 2003-10-09 Integriderm Inc Acide hydroxamique et ses derives comme inhibiteurs de la melanocyte tyrosinase pour eclaircissants topiques de la peau
US9663453B2 (en) 2014-10-30 2017-05-30 Universidad De Antofagasta Metabolites and oximes with vasodilator and hypotensive activity
BE1026073B1 (nl) * 2018-03-05 2019-10-07 Purna Pharmaceuticals Nv Verbeterde werkwijze voor het maken van een farmaceutische emulsie

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