EP1877046A2 - Utilisation de piegeurs de radicaux dans une preparation topique pour un traitement antipyretique - Google Patents

Utilisation de piegeurs de radicaux dans une preparation topique pour un traitement antipyretique

Info

Publication number
EP1877046A2
EP1877046A2 EP06755030A EP06755030A EP1877046A2 EP 1877046 A2 EP1877046 A2 EP 1877046A2 EP 06755030 A EP06755030 A EP 06755030A EP 06755030 A EP06755030 A EP 06755030A EP 1877046 A2 EP1877046 A2 EP 1877046A2
Authority
EP
European Patent Office
Prior art keywords
preparation
acid
radical
substances
derivatives
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.)
Ceased
Application number
EP06755030A
Other languages
German (de)
English (en)
Inventor
Karin Golz-Berner
Leonhard Zastrow
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Coty Prestige Lancaster Group GmbH
Original Assignee
Coty Prestige Lancaster Group GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Coty Prestige Lancaster Group GmbH filed Critical Coty Prestige Lancaster Group GmbH
Publication of EP1877046A2 publication Critical patent/EP1877046A2/fr
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/18—Antioxidants, e.g. antiradicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • the present invention relates to the use of one or more radical-scavenging substances as therapeutically active substances in a topical preparation for antipyretic treatment.
  • the invention also provides the use of radical scavenging substances as active ingredients in a combination preparation for the treatment of fever, wherein the combination preparation comprises a topical preparation and an oral preparation in a free combination and both preparations independently contain one or more free radical scavenging substances.
  • the two preparations of the combination preparation are provided according to the invention for simultaneous, separate or time-graded administration.
  • Fever is a physiological condition characterized by an increase in body temperature. With 38 to 38.5 0 C is called moderate fever, at 39 to 40.5 0 C by high fever and also of a very high fever.
  • salicylates characterized by acetylsalicylic acid (for example aspirin) are the most widely used antipyretic agents.
  • aspirin is in principle well tolerated by most people, a number of toxic side effects are associated with its use, namely salicylate-induced gastric ulcers and sometimes gastrointestinal bleeding.
  • the para-aminophenol derivatives acetaminophen and phenacetin are alternatives to aspirin with respect to their antipyretic action, with acetaminophen a somewhat has lower toxicity than phenacetin and also does not show the undesirable side effects of aspirin.
  • acetaminophen there is a risk of hepatic necrosis if it is acutely overdosed. In chronic overdose hemolytic anemia may occur as a form of acute toxicity.
  • the object of the invention was to find alternative active ingredients for fever treatment.
  • the object is achieved by providing a topically applicable preparation form containing radical-scavenging substances or substance mixtures.
  • Antioxidants with a certain capacity to catch free radicals can not only be reduced, but at the same time a fever-lowering effect is effected.
  • particularly suitable are those topical preparations whose radical protection factor is at least 250 ⁇ 10 14 radicals per mg of preparation, measured by determining the number of free radicals of a solution of a test substance (Si) by means of electron spin resonance (ESR) in comparison with the ESR measurement result of the preparation after the relationship
  • the Radical protection factor 800 ⁇ 10 14 radicals per mg of preparation, particularly preferably 30 000 ⁇ 10 14 radicals per mg of preparation.
  • the radical protection factor indicates the activity for binding of free radicals by an antioxidant or a radical scavenger to a test substance.
  • the radical scavenger or the z. B. be applied in a dermatological preparation on the skin.
  • compositions of the invention in addition to the (n) radical scavenger (s) further dermatological excipients and carriers, as they are commonly used in such preparations, for.
  • water preservatives, dyes, thickeners, moisturizing substances, alcohols, polyols, electrolytes, gel formers, polar and nonpolar oils, polymers, copolymers, emulsifiers, stabilizers, fillers.
  • these are coated with at least one pharmaceutically acceptable excipient and optionally other excipients to solid formulations such as creams, gels, ointments or emulsions or liquid formulations such as solutions, suspensions , Lotions, rinses, serums or oils in usually formulated.
  • Suitable bases for ointments, creams or gels are, for example, petroleum jelly, paraffins such as hard paraffin or thick paraffin, medium-chain triglycerides, natural waxes, wool wax, isopropyl myristate, fumed silica, bentonite, starch, alginates, cellulose and cellulose ethers, sodium carboxymethylcellulose, polyethylene glycols and others.
  • Suitable solvents for lotions and solutions are water or water-alcohol mixtures.
  • liposomes, cyclodextrins or nanoparticles which ensure optimum transport of the antioxidants into the skin can also serve as carrier systems for the antioxidants.
  • Transdermal systems are also considered as topical preparations, for example adhesives, patches or dressings which contain the antioxidants together with a carrier.
  • Useful carriers may contain absorbable, pharmacologically acceptable solvents to aid in the passage of the antioxidants through the skin.
  • Solvents which ensure good penetration of the radical-scavenging substances into the skin are, for example, the alcohols phenylethanol-1, glycerol or ethanol or mixtures thereof.
  • the topical preparations contain stabilizers for the antioxidants.
  • Advantageous therapeutic preparations are also aqueous systems in the form of tinctures or baths, or dry substances intended for the preparation of baths.
  • all generally known enzymatic and non-enzymatic antioxidants can be used as radical-scavenging substances, provided that they can be formulated into a preparation to be applied dermal and have a corresponding radical protection factor.
  • the antioxidants used are, for example, selected from the group of vitamins consisting of tocopherols and their derivatives, especially ⁇ -
  • Tocopherol or ⁇ -tocopheryl ester especially tocopheryl acetate, Tocopheryl acylate, laurate, myristate, palmitate, oleate or linoleate; Vitamin A and its derivatives, especially retinyl palmitate; Vitamin C and its derivatives, especially isoascorbate, (2- or 3- or 6-) o-alkylascobic acids, ascorbic acid esters, such as ascorbyl acetates, ascorbyl phosphates, 6-o-lauroyl, myristoyl, palmitoyl, oleoyl or linoleoyl L-ascorbic acid; Folic acid and its derivatives.
  • flavonoids comprising flavones, flavonols, flavanonals and chacones, in particular citrus flavonoids, for example rutin, naringin and neohesperidin; Carotenoids and carotenes such as ⁇ -carotene and ⁇ -carotene; ⁇ -lipoic acid, lipoic acid amide; Amino acids such as histidine, glycine, tyrosine, tryptophan and amino acid derivatives; ⁇ -hydroxy acids such as citric acid, lactic acid, malic acid; Uric acid and its derivatives; Rutinic acid, ⁇ -glucosylrutin; Phenolic carboxylic acids such as rosmarinic acid or ferulic acid; humic acid; Bile acids and bile acid derivatives such as methyl, ethyl, propyl, amyl, butyl and la
  • RPF complex The preparations described in WO 99/66881, WO 01/26617 and DE 103 25 156 A1 from plant extracts with a high radical protection factor, which are referred to as RPF complex, can also be used as antioxidants in the present invention.
  • plant extracts are acerola extract, citrus peel or leaf extract (Citrus bigaradia, Citrus hystrix, Citrus aurantifolia, Citrofurtunella microcarpa, Citrus aurantium, Citrus reticulata), bitter orange extract (peel or fruit), cherry extract of the Spanish cherry Cherry, kiwi extract (Actinidia chinensis), papaya fruit extract (Caricae papayae), tea extract [leaves of green or black tea, leaves or bark of New Jersey tea (Ceanthus velutinas)], coffee bean extract of green or roasted beans, Prunus extracts, e.g.
  • Prunus armeniaca Prunus dulcis, Prunus persica, Prunus domestica, Prunus spinosa, Prunus serotina, Prunus virginiana, extracts of the bark of the Mexican skin tree (Mimosa tenuiflora), Angelica root extract (Angelica archangelica), Pongamia pinnata extract, tomato extract Der Content of these plant extracts in the topical preparation may be between 0.05 and 45% by weight, preferably 0.1 to 40% by weight, in particular 1.5 to 20% by weight, and mixtures of these extracts may also be present in the preparation of active compound , The concentration depends on the radical protection factor of the extract or radical scavenger. Thus, extracts with very high radical protection factors from 10,000 to 90,000 may be present in relatively low concentrations of 0.1% by weight, provided that they maintain the corresponding radical protection factor for longer periods of several weeks to months.
  • radical scavengers of 3-33% by weight, in particular 12-26% by weight, based on the total weight of the topical preparation.
  • the radical protection factor of the preparation is at least 300 ⁇ 10 14 radicals per mg of preparation, in particular at least 800 ⁇ 10 14 radicals per mg, particularly preferably at least 1400 ⁇ 10 14 radicals per mg.
  • Embodiments of the invention in which the radical protection factor of the preparation is from 1500 to 30,000 x 10 14 radicals per mg of preparation are especially preferred.
  • the concentration of radical scavenger or radical scavenging mixture in the range from 5 to 40% by weight is preferred, in particular in the range from 8 to 35% by weight, based on the total weight of the preparation.
  • the enzymatic antioxidants such as superoxide dismutase and metal complexes having similar activity as, for example, catalase and glutathione peroxidase.
  • RPF complex I of WO99 / 66881 (e.g., example 1 or 2) or WO 01/26617.
  • RPF complex I of WO99 / 66881 (e.g., example 1 or 2) or WO 01/26617.
  • This consists of a preparation of active compound containing in a product obtained by extraction of the bark of Quebracho blanco and subsequent enzymatic hydrolysis product containing at least 90% by weight of proanthocyanidin oligomers and at most 10% by weight of gallic acid, in microcapsules, and a through Extracting silkworm extract containing the peptide cecropins, amino acids and a vitamin mixture, and a nonionic, cationic or anionic hydrogel or mixture of hydrogels, and one or more phospholipids and water (RPF 2400), optionally supplemented by cyclodextrins and Yeast digestion product (RPF 4800) described below.
  • One advantageous free radical scavenger is also a mixture of enzymes and vitamins, specifically a obtained by ultrasonic decomposition product of a yeast, wherein the digestion product SOD, protease, vitamin B 2, vitamin B 6, vitamin B 2, vitamin D 2 and vitamin E contains. Preferably, it contains at least 150 U / ml SOD, protease and vitamins B and D, with the ratio SOD: protease as international units at least in the range of 3: 1 to 8: 1 (RPF 2020 x 10 14 radicals / mg).
  • the preparation of the enzyme / vitamin mixture is carried out via a digestion method by means of ultrasound, which is described in DE 4241154C1 and in which an ultrasonic flow cell cell dispersion or suspension is passed through a sound room in which the sonotrode in half to two-thirds of their length in the Flow cell protrudes and immersed in the medium to be sonicated.
  • the sonotrode has an angle of 80.5 to 88.5 °, and the ratio immersion length of the sonotrode in mm to the sonication volume in ml is set to a value of 1: 1, 1 to 1: 20.
  • the solids content in the medium to be sonicated is in the range of 1: 0.02 to 1: 2.2 (wt.%).
  • AIs cell dispersion may include yeasts such as baker's yeast, brewer's yeast, wine yeast and specially treated yeasts such.
  • yeasts such as baker's yeast, brewer's yeast, wine yeast and specially treated yeasts such.
  • B. SOD-enriched yeasts are used.
  • An advantageously used cell dispersion contains z.
  • z. B. 1-10% by weight of such a yeast digestion product from baker's yeast or bio-yeast can synergistically increase an already existing radical protection factor of another oxidizing agent.
  • Other preferred radical scavengers include (in brackets the RPF values without the suffix "x10 14 radicals / mg") tomato extract (1000); carrot extract (300); RPF complex + vitamin E in cyclodextrin (7200); stabilized vitamin C (8290 Yeast yeast digestion product from baker's yeast (2020); rapeseed extract (67,000); RPF complex I in cyclodextrins (720); Origano oil (Origanox) (90306); Origanum vulgare extract (80000); Tannic acid (310000); Pine bark extract (12500); Himothatus sucruba extract (700); Emplica® (Merck) (42400); grape skin white (53000); grape skin red (95100); flavonoid extract of red wine (6000); rosmarinic acid (36000-68000); Curry extract (12500); saffron extract (900); orange peel extract (24000); rapeseed oil (2550); strawberry oil (1300); green tea extract (21500); grapefruit extract (53000); sodium ascorbyl phosphat
  • the topical preparation contains the free-radical scavenger or radical scavenger mixture encapsulated in conventional liposomes or in asymmetric lamellar aggregates.
  • These aggregates consist of phospholipids and oxygen-loaded fluorocarbon or fluorocarbon mixture.
  • Their content of fluorocarbon is in the range of 0.2 to 100% weight / volume, the phospholipid one Phosphatidylcholin content of preferably more than 30 to 99% by weight, and wherein these aggregates a skin penetration depending on the critical solubility temperature of the fluorocarbons
  • Aggregates are oxygen carriers and allow penetration of the oxygen into the skin and thus better supply of the skin with oxygen. It may also contain aggregates in the preparation, which are loaded only with oxygen and thereby still support the action of the radical scavenger.
  • These aggregates are prepared by high-pressure homogenization of phospholipids such as soybean lecithin and egg lecithin or synthetic phospholipids or partially hydrogenated phospholipids having a phosphatidylcholine content of more than
  • Carbon compounds or mixtures thereof capable of producing gases such as
  • lysolecithins in the concentration range from 0.1 to 10% by weight and / or charged phospholipids such as phosphatidylethanolamine, n-acetylphosphatidylethanolamine or phosphatidic acid in the concentration range from 0.1 to 30% by weight can be present therein on the total weight of the aggregates.
  • these phospholipid-stabilized aggregates carry in their core hydrophobic fluorocarbons which are capable of transporting oxygen.
  • Their surface-chemical stabilization is primarily by a monolayer with inverse arrangement and optionally a subsequent construction of bilayer layers. Because of the peculiarity of their structural arrangement, these aggregates are referred to as asymmetric lamellar oxygen carriers.
  • Their exceptional colloid-chemical stability is probably due to the lamellar structure and surface charge of the aggregates. The latter is due to the selection of suitable phospholipids or their mixtures of natural as well as synthetic provenance. In the first place, phospholipids, in particular phosphatidylcholine, are responsible for a beneficial effect in this sense.
  • the mentioned effect of the phospholipids is verified by corresponding negative Zeta potentials and by the measurement of charge densities (in the case of a titration with a cationic polyelectrolyte).
  • Essential for the use of the fluorocarbon aggregates is the skin penetration as a function of the critical solubility temperature of the selected fluorocarbons or fluorocarbon mixtures (for the use of asymmetric lamellar aggregates see also DE-B-4221255.
  • fluorocarbons perfluorinated or highly fluorinated carbon compounds or mixtures capable of transporting gases such as oxygen and carbon dioxide.
  • Highly fluorinated hydrocarbon compounds are for the purposes of this invention, those in which most of the hydrogen atoms are replaced by fluorine atoms, so that further replacement does not necessarily increase the gas transportability. This is usually achieved when approximately up to 90% of the hydrogen atoms are replaced by fluorine atoms.
  • fluorocarbons in which at least 95% of the hydrogen atoms have been replaced, more preferably 98%, and most preferably 100%. It can be used a variety of fluorocarbons, z.
  • fluoroalkanes mono- or bicyclic and optionally fluoroalkyl-substituted fluorocycloalkanes, perfluorinated aliphatic or dicyclic amines, bis (perfluoroalkyl) ethenes, perfluoropolyethers or mixtures thereof.
  • fluorocarbons as perfluorodecalin, F-butyltetrahydrofuran, perfluorotributylamine, perfluorooctyl bromide, bis-fluoro (butyl) -ethene or bis-fluoro (hexyl) ethene or C ⁇ -Cg-perfluoroalkanes.
  • the topical preparation of the invention may further contain humectants such as glycerol, butylene glycol, propylene glycol or mixtures thereof.
  • liposomes can also be used as a transport system for the modified kaolin-containing mixture within the preparation according to the invention.
  • Liposomes are completely closed lipid bilayer membranes that contain an aqueous volume. Liposomes can be unilamellar vesicles (having a single-membrane bilayer) or multilamellar vesicles (onion-like structures characterized by multiple membrane bilayers, each separated from the next by an aqueous layer).
  • the bilayer consists of two lipid monolayers that have a hydrophobic "tail” region and a hydrophilic "head region.”
  • the structure of the membrane bilayer is such that the hydrophobic (nonpolar) "tails" of the lipid monolayers are directed towards the Center of the bilayer orientate, while the hydrophilic "heads” oriented towards the aqueous phase.
  • phospholipids As phospholipids z. As are used phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidic acid and lysolecithins and mixtures thereof. Well-known products are, for example, Phoslipon® or Nat®.
  • oils used in the preparation of the invention may be conventional cosmetic oils, such as a mineral oil; hydrogenated polyisobutene; synthetic or natural-made squalane; cosmetic esters or ethers, which may be branched or unbranched, saturated or unsaturated; vegetable oils; or mixtures of two or more thereof.
  • oils are, for example, silicone oils, mineral oils, hydrogenated polyisobutene, polyisoprene, squalane, tridecyl trimellitate, trimethylpropane triisostearate, isodecyl citrate, neopentyl glycol diheptanoate, PPG-15-stearyl ether and also vegetable oils, such as calendula oil, jojoba oil, avocado oil, macadamia nut oil, castor oil, Cacao butter, coconut oil, corn oil, cottonseed oil, olive oil, palm kernel oil, rapeseed oil, safflower oil, sesame seed oil, soybean oil, sunflower seed oil, wheat germ oil, grape seed oil, kukui nut oil, thistle oil and mixtures thereof.
  • the dermatological properties of the solid composition are influenced, such as degree of transparency, softness, hardness, spreading effect.
  • the formulations of the invention may be in the form of O / W or W / O emulsions.
  • Suitable emulsifying agents for O / W emulsions are for example addition products of 2-30 mol of ethylene oxide onto linear C 8 -C 22 fatty alcohols, Ci2 to C-2 2-fatty acids and C 8 -C 5 alkyl phenols; C 2 -C 2 2-fatty acid mono- and diesters of addition products of 1-30 mol of ethylene oxide onto glycerol.
  • Suitable emulsifiers for W / O emulsions are, for example, adducts of 2-15 moles of ethylene oxide with castor oil; Esters of C12-C22 fatty acids and glycerine, polyglycerol, pentaerythritol, sugar alcohols (eg sorbitol), polyglucosides (eg cellulose); polyalkylene glycols; Lanolin alcohol; Copolymers of polysiloxane-polyalkylpolyethers.
  • the radical protection factor determines the activity of a substance for binding free radicals to a test substance.
  • This test substance consists of a highly reactive, semi-stable radical that reacts with all known antioxidants.
  • radicals include nitroxides such as Proxo (2,2,5,5-tetramethyl-1-dihydropyrrolineoxy-nitroxide), Tempol (2,2,6,6-tetramethyl-1-piperidinoxy-4-ol-nitroxide), DTBN (Di-tert-butyl-nitroxide or preferably DPPH (1,1-diphenyl-2-picryl-hydrazyl.
  • the measurement of the RPF is made by measuring the signal amplitude of the test radical by electron spin resonance (ESR / EPR) before and after mixing with an antioxidant / free radical scavenger and calculating the RPF therefrom.
  • RPF is known for a number of standard antioxidants, for all-trans retinol at 827, all-trans retinol acetate at 196; for DL- ⁇ -tocopherol at 41200 and for ⁇ -tocopheryl acetate at 48, respectively x 10 14 radicals / mg.
  • the exact measuring method for the radical protection factor is described by Herrling, Groth, Fuchs and Zastrow in Conference Materials "Modern Challenges To The Cosmetic Formulation" 5.5.-7-5.97, Dusseldorf, pp.
  • test substance here: DPPH
  • free radicals radicals per ml
  • a signal amplitude Si is measured by means of an ESR spectrometer.
  • the test radical like the antioxidant, is dissolved in a (eg 0.1 M) water / alcohol solution. Then the signal amplitude S 2 of the antioxidant is measured.
  • the normalized difference between the two signal amplitudes is the reduction factor RF.
  • the result of the radical reduction of the test substance RC x RF is normalized to the amount of product input PI (mg / ml).
  • RC is the amount of the test substance, i. the known number of radicals of the test substance.
  • the radical protection factor is calculated according to the following equation
  • RPF N x 10 14 [radicals per mg], where N is a positive real number, and the RPF can be simplified down to the numerical value of N. This shortening is used in the examples of the present invention.
  • the radical protection factor can be determined by means of an ESR spectrometer (GALENUS GmbH, Berlin, Germany) and is a size for labeling products in terms of their ability to bind free radicals.
  • the method is an in vitro method in which no individual properties of the user affect the antioxidants.
  • Cyclodextrins (Wacker chemistry) or mixtures thereof can be used. Cyclodextrins are known as encapsulating materials for pharmaceutical and cosmetic active ingredients and can therefore also be used here for the encapsulation of radical scavengers.
  • the above-mentioned topical preparations contain the radical-scavenging substances in a therapeutically effective amount. This can depend on various factors such as gender, age and individual
  • Embodiment of the invention are in the final preparation 5-45 wt.%
  • Antioxidant preferably 5-40 wt.%, Particularly preferably 10-35 wt.%, In particular 10-20 wt.%, Based on the total weight of
  • the topical pharmaceutical preparation is applied 2 to 6 times daily, for example, as a gel or cream, with one to two hours to wait before a repeat after the first application.
  • the topical preparation is applied hourly.
  • the application can be carried out preferably on the calves, on the arms and / or on the back.
  • a cut of up to 1-3 0 C is after hours, at the latest by 1 to 2 days with a high fever of 39 to 40.5 0 C achieved.
  • the present invention therefore also relates to the described use of said radical-scavenging substances in combination with the simultaneous oral administration of known antipyretics.
  • the dose of these antipyretics can be reduced by 30-70%.
  • the invention also relates to a method for antipyretic treatment, characterized in that a therapeutic preparation comprising a therapeutically effective amount of a radical-scavenging substance or a mixture of radical-scavenging substances on the human skin in a preferred amount of at least 2 mg / cm 2 , more preferably 2-10 mg / cm 2 , is applied.
  • a therapeutic preparation comprising a therapeutically effective amount of a radical-scavenging substance or a mixture of radical-scavenging substances on the human skin in a preferred amount of at least 2 mg / cm 2 , more preferably 2-10 mg / cm 2 , is applied.
  • the topical preparation is applied to the arms, legs and / or back, preferably for at least 4 hours to 2 days.
  • the radical protection factor of the preparation should be at least 250 x 10 14 radicals per mg of preparation.
  • the simultaneous administration of oral antipyretics can take place.
  • the administered dose of oral antipyretics is reduced by 30-70%.
  • Another object of the invention is the use of radical scavenging substances as therapeutically active substances for the preparation of a combination preparation for antipyretic treatment comprising a topical preparation and an oral preparation in a free combination, each preparation comprising one or more radical-scavenging substances.
  • the invention also relates to the combination preparation itself.
  • the oral preparation contains 5-20% by weight, in particular 5-15% by weight (based on the total weight of the oral preparation) radical-catching substance (s).
  • the radical-scavenging substances of the oral preparation are selected from the group of vitamins consisting of tocopherols and their derivatives, especially ⁇ -tocopherol; Vitamin A and its derivatives, especially retinyl palmitate; Vitamin C and its derivatives, especially isoascorbate, (2- or 3- or 6-) o-alkyl ascorbic acids, ascorbic acid esters, such as ascorbyl acetates, ascorbyl phosphates, 6-o-lauroyl, myristoyl, palmitoyl, oleoyl or linoleoyl L-ascorbic acid; Folic acid and its derivatives and mixtures thereof.
  • vitamins consisting of tocopherols and their derivatives, especially ⁇ -tocopherol
  • Vitamin A and its derivatives especially retinyl palmitate
  • Vitamin C and its derivatives especially isoascorbate, (2- or 3- or 6-) o-alkyl ascorbic acids, ascorbic acid esters,
  • the radical-scavenging substances of the oral preparation may also be selected from the group consisting of flavonoids comprising flavones, flavonols, flavanonals and chacones, especially citrus flavonoids such as rutin, naringin and neohesperidin; Carotenoids and carotenes such as ⁇ -carotene and ⁇ -carotene; ⁇ -lipoic acid, lipoic acid amide; Amino acids such as histidine, glycine, tyrosine, tryptophan and amino acid derivatives; ⁇ -hydroxy acids such as citric acid, lactic acid, malic acid; Rutinic acid, ⁇ -glucosylrutin; Phenolcarbon Acid such as rosmarinic acid or ferulic acid.
  • flavonoids comprising flavones, flavonols, flavanonals and chacones, especially citrus flavonoids such as rutin, naringin and neohesperi
  • oral preparation of the combination preparation according to the invention for example tablets, film-coated tablets, dragées, capsules, pills, powders, solutions or suspensions, also as depot form, are used.
  • Dosage forms as tablets can be obtained, for example, by mixing the radical scavenger with known excipients, such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or agents, which can achieve a depot effect, such as carboxypolymethylene, Carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate.
  • the tablets can also consist of several layers.
  • Dragees can be prepared analogously by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the dragee wrapper can also consist of several layers, whereby, for example, the abovementioned auxiliaries are used.
  • the capsules can be prepared by mixing the active ingredient with carriers such as lactose or sorbitol, which are then placed in capsules.
  • solutions, dispersions or suspensions with the radical scavenger can be added to improve the taste with substances such as saccharin, cyclamate or sugars, and / or with flavorings such as vanillin or orange extract. Furthermore, they may be mixed with suspending aids, such as sodium carboxymethylcellulose, or preservatives, such as p-hydroxybenzoic acid.
  • the topical preparation of the free combination contains the above-mentioned radical-scavenging substances in the quantities also mentioned above.
  • the present invention thus also provides a process for the antipyretic treatment of a human, in which a topical preparation which comprises a therapeutically effective amount of one or more radical-scavenging substances is applied to the skin of the human and simultaneously or sequentially an oral preparation containing a therapeutic effective amount of one or more radical scavenging substances is applied.
  • the oral preparation for. As the tablet, should preferably simultaneously with the start of topical application, for. B. in the morning, and if necessary be repeated at noon and / or in the evening, preferably at least in the evening.
  • the oral dose of free radical scavenger (s) per day for an adult is between 20-170 mg, preferably 100-150 mg. This dose can be spread over 2 to 3 doses per day.
  • RPF complex 1 10.0 shell extract of red
  • phase 1 according to WO99 / 66881 (active substance complex according to Example 1).
  • the separately prepared phases A and B are heated to 75 0 C and combined with stirring.
  • the mixture is cooled to about 45 0 C, and the phase C is added with stirring.
  • Then is cooled to 4O 0 C.
  • phase D while stirring
  • phase E is finally added at 35 ° C., and the mixture is stirred until homogeneous.
  • RPF 4990 x 10 14 rad./mg.
  • Vitamin C stabilizes 9.5
  • Example 1 The cream of Example 1 was applied to arms and legs of a drug-free 62 year old man with allergy to antipyretics. The body temperature of the man fell after 2 hours from 39.4 0 C to 38.5 0 C and after a further 2 hours to 38.1 0 C. There was no skin irritation on.
  • Example 1 The cream of Example 1 was applied to the arms, legs and back of a 26-year-old woman 24 hours after discontinuation of an antipyretic agent.
  • the body temperature of the woman fell after 3 hours from 39.7 0 C to 39, 0 0 C and after a further 3 hours to 38.6 0 C. There was no skin irritation on.
  • Example 2 The cream of Example 2 was applied to arms, legs and back of a 38-year-old woman.
  • Example 6 The cream of Example 2 was applied on arms, legs and back to seven volunteers with fever between 39, 0 0 C and 39.4 0 C per hour. After three hours, the fever had fallen by 0.5-0.6 0 C and after another two hours again by 0.3-0.4 0 C.
  • a tablet was prepared with the following composition of radical scavengers: vitamin C 98mg, vitamin E 22mg, niacin 15mg, pantothenic acid B 5 2mg, beta-carotene 7mg, vitamin B6 1, 7mg, vitamin B2 1, 4mg, folic acid 0.3mg, vitamin B1 1, 1 mg, vitamin B12 3 mg, excipients: microcrystalline cellulose, magnesium stearate, sorbitol and corn starch.
  • radical scavengers vitamin C 98mg, vitamin E 22mg, niacin 15mg, pantothenic acid B 5 2mg, beta-carotene 7mg, vitamin B6 1, 7mg, vitamin B2 1, 4mg, folic acid 0.3mg, vitamin B1 1, 1 mg, vitamin B12 3 mg, excipients: microcrystalline cellulose, magnesium stearate, sorbitol and corn starch.
  • Example 1 The cream of Example 1 was applied to ten subjects with a fever between 39.2 0 C and 39.4 0 C every hour on the arms, legs and back. In parallel, five subjects were each given a tablet according to Example 7 with the start of the topical application. The other five subjects received no tablet.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Toxicology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Cosmetics (AREA)

Abstract

La présente invention concerne l'utilisation d'un ou de plusieurs piégeurs de radicaux comme substances thérapeutiquement actives dans une préparation topique pour un traitement antipyrétique. Cette invention concerne également l'utilisation de piégeurs de radicaux comme principes actifs dans une préparation combinée destinée à traiter la fièvre, cette préparation combinée comprenant une préparation topique et une préparation orale librement combinées et ces deux préparations contenant, indépendamment l'une de l'autre, un ou plusieurs piégeurs de radicaux libres. Selon ladite invention, les deux préparations de la préparation combinée sont prévues pour être administrées simultanément, séparément ou de manière échelonnée dans le temps.
EP06755030A 2005-05-04 2006-05-04 Utilisation de piegeurs de radicaux dans une preparation topique pour un traitement antipyretique Ceased EP1877046A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005021806A DE102005021806A1 (de) 2005-05-04 2005-05-04 Verwendung von radikalfangenden Substanzen zur Behandlung von Zuständen mit erhöhter Hauttemperatur, insbesondere zur antipyretischen Behandlung
PCT/EP2006/062075 WO2006117404A2 (fr) 2005-05-04 2006-05-04 Utilisation de piegeurs de radicaux dans une preparation topique pour un traitement antipyretique

Publications (1)

Publication Number Publication Date
EP1877046A2 true EP1877046A2 (fr) 2008-01-16

Family

ID=36649658

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06755030A Ceased EP1877046A2 (fr) 2005-05-04 2006-05-04 Utilisation de piegeurs de radicaux dans une preparation topique pour un traitement antipyretique

Country Status (5)

Country Link
US (1) US20090081285A1 (fr)
EP (1) EP1877046A2 (fr)
JP (1) JP2008540386A (fr)
DE (1) DE102005021806A1 (fr)
WO (1) WO2006117404A2 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2905028B1 (fr) * 2006-08-21 2008-12-19 Commissariat Energie Atomique Dispositif de memoire electrochimique
CN101583369B (zh) 2006-11-15 2015-03-11 关节炎缓痛补充剂有限公司 局部制剂及其用途
AU2011227202A1 (en) * 2010-03-17 2012-10-04 Arbonne International Llc Oral supplement
EP2575456B1 (fr) * 2010-05-28 2016-05-04 Galderma S.A. Compositions et procédés destinés au traitement d'ecchymoses

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4636516A (en) * 1981-02-19 1987-01-13 Yamanouchi Pharmaceutical Co., Ltd. 3,5-di-tert-butyl-4-hydroxyphenyl-substituted heterocyclic compounds
JPS60209515A (ja) * 1984-04-03 1985-10-22 Hokuriku Seiyaku Co Ltd 消炎鎮痛クリ−ム剤
FR2649322A1 (fr) * 1989-07-04 1991-01-11 Natura Medica Laboratoires Complexes biodisponibles d'acide (alpha)-linolenique, extraits de plantes en contenant et compositions pharmaceutiques les incorporant
GB9215665D0 (en) * 1992-07-23 1992-09-09 British Bio Technology Compounds
DE19860754B4 (de) * 1998-06-24 2004-10-28 Coty B.V. Kosmetische Zubereitung
CN1255095C (zh) * 1999-10-08 2006-05-10 科蒂股份有限公司 含有协同增加自由基防护因数的活性物质的美容用制剂
IL137559A (en) * 2000-07-27 2006-12-31 Amnon Sintov A system for administering drugs through the skin
JP2004300107A (ja) * 2003-04-01 2004-10-28 Aikusu Lab Sangyo:Kk 経皮消炎鎮痛剤組成物
DE10325156A1 (de) * 2003-05-28 2004-12-23 Coty B.V. Wirkstoffzubereitung mit Pflanzenextrakten für Kosmetika
DE10325158A1 (de) * 2003-05-28 2004-12-23 Coty B.V. Kosmetikum für die Remineralisierung und Anti-Alterungsbehandlung der Haut

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006117404A2 *

Also Published As

Publication number Publication date
US20090081285A1 (en) 2009-03-26
JP2008540386A (ja) 2008-11-20
DE102005021806A1 (de) 2006-11-16
WO2006117404A2 (fr) 2006-11-09
WO2006117404A3 (fr) 2007-06-28

Similar Documents

Publication Publication Date Title
CN112891241B (zh) 一种靶向线粒体皮肤抗衰纳米组合物及其制备方法和应用
JP5191988B2 (ja) エステル化レシチンを用いたナノリポソーム及びその製造方法、及びこれを含む皮膚疾患の予防又は治療用組成物
EP1513492B1 (fr) Microemulsions presentant une differentiabilite de phase binaire et de substance active, leur production et leur utilisation en particulier pour administrer de l'oxygene par voie topique
EP2320754B1 (fr) Microémulsion
EP1372601B1 (fr) Preparation cosmetique renfermant de la vitamine a
Suryawanshi Phytosome: an emerging trend in herbal drug treatment
DE10361067A1 (de) Medikamentöse Lipolyse von Fettansammlungen
KR20180131876A (ko) 리포좀 기술을 이용한 안정화된 세라마이드 복합물 및 그 제조 방법 및 이를 함유하는 화장료 조성물
DE102010013064A1 (de) Neuartiges Trägersystem für den Transport von Wirkstoffen in die Haut
WO2008119097A1 (fr) Agent pharmaceutique contre les démangeaisons et la douleur
US10967036B2 (en) Composition comprising an onion extract and liposomes
EP1877046A2 (fr) Utilisation de piegeurs de radicaux dans une preparation topique pour un traitement antipyretique
KR20220159075A (ko) 피부모사 리포좀 및 보습효능을 포함하는 이의 용도
TR202008828A2 (tr) Kozmeti̇k formüllerde kullanmak üzere li̇pozomal teknoloji̇ i̇le enkapsüle edi̇lmi̇ş yabani̇ i̇ğde (hippophae rhamnoides) ekstresi̇ni̇n elde edi̇lme yöntemi̇
DE102006040450B3 (de) Verwendung einer Zusammensetzung für die Hautbehandlung nach Röntgenbestrahlung
KR101967576B1 (ko) 라멜라 리포좀으로 안정화된 백장미 추출물을 포함하는 항아토피, 항균 및 항염증용 화장료 조성물
KR20200126208A (ko) 경피 전달용 신규한 슈도 세라마이드 리포좀
KR101208120B1 (ko) 비타민 복합체, 이를 제조하는 방법 및 이를 포함하는 화장료 조성물
KR102632236B1 (ko) 리포좀 복합체 및 이를 포함하는 피부 개선용 화장료 조성물
KR102246331B1 (ko) 흰소나무 솔방울 추출물을 포함하는 나노 입자 및 이의 제조방법
KR20220152865A (ko) 안정성이 향상된 리기다 소나무 껍질 추출물 봉입 나노 입자 및 제조방법, 이를 함유하는 화장료 조성물
DE202023100649U1 (de) Dispersion und Zubereitung zur topischen Anwendung
KR20130017192A (ko) 리조레시친 및 글리세로포스포콜린을 이용한 리포좀 제제, 및 이를 포함하는 퍼스널 케어 조성물
DE102015004672A1 (de) In Vesikeln formulierte Naturstoffkombination

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20071116

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK YU

DAX Request for extension of the european patent (deleted)
RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 36/64 20060101ALI20080707BHEP

Ipc: A61K 36/36 20060101ALI20080707BHEP

Ipc: A61K 36/232 20060101ALI20080707BHEP

Ipc: A61K 36/48 20060101ALI20080707BHEP

Ipc: A61K 36/74 20060101ALI20080707BHEP

Ipc: A61K 36/82 20060101ALI20080707BHEP

Ipc: A61P 29/00 20060101AFI20080707BHEP

17Q First examination report despatched

Effective date: 20080716

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 20101021