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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents

Definitions

• antihistaminic compounds for the treatment of skin diseases, such as pruritus or insect bites, is known in the art.
• the invention relates to the topical use of a topically applicable antihistaminic compound in combination with a terpenoid compound (for the manufacture of a topical medicament) for the treatment of allergic and inflammatory skin diseases.
• Allergic and inflammatory skin diseases are, for example, pruritus, insect bites, sunburn, others burns, urticaria, eczema, neurodermitis, atopic dermatitis or contact dermatitis.
• ahistan etymemazine, fenethazine, N-hydroxyethylpromethazine chloride, isopromethazine, mequitazine, methdilazine, promethazine, pyrathiazine, thiazinamium methylsulfate or trimeprazine;
• a tricyclic other than phenothiazines e.g. azatadine, clobenzepam, cyproheptadine, deptropine, isothipendyl, loratadine or prothipendyl; and
• an antihistaminic compound of another structure e.g.
• antazoline astemizole, azelastine, cetoxime, clemizole, clobenztropine, diphenazoline, diphenhydramine, ebastine, emedastine, levocabastine, mebhydroline, phenindamine, terfenadine or tritoqualine.
• topically applicable antihistaminic compound is to be understood as also to include (1 ) any topically acceptable salt of a free compound (acid or base) mentioned above, (2) any free compound (acid or base) or any other topically acceptable salt of a salt mentioned above, and (3) any active metabolite of a compound mentioned above.
• active metabolites are carebastine, which is the active metabolite of ebastine; norastemizole, which is the active metabolite of astemizole, or terfenadine carboxilate, which is the active metabolite of terfenadine.
• a topically acceptable salt of an antihistaminic compound having a basic group is e.g. an acid addition salt.
• Suitable acid components may be, for example, strong inorganic acids, typically mineral acids, e.g. sulfuric acid, phosphoric acids, e.g. orthophosphoric acid, hydrohalic acids, e.g. hydrochloric acid, or strong organic carboxylic acids, typically lower alkanecarboxylic acids which may be substituted, e.g. by halogen, such as acetic acid or trifluoroacetic acid, dicarboxylic acids which may be unsaturated, e.g.
• a topically acceptable salt of an antihistaminic compound having an acidic group is e.g. an alkali metal or alkaline earth metal salt, e.g. the sodium, potassium, magnesium or calcium salt, an aluminium salt or a transition metal salt, e.g. the zinc or copper salt, or a corresponding salt with ammonia or organic amines.
• Organic amines that come into consideration are, for example, the following: alkylamines, such as mono-, di- or tri-lower alkylamines, e.g.
• alkyienediamines such as lower alkylenediamines, e.g. ethylenediamine, alkylamines substituted by phenyl, such as mono- or di-phenyl-lower alkylamines, e.g. benzylamine or 1- or 2-phenylethylamine, hydroxy-alkylamines, such as mono-, di- or tri-hydroxy-lower alkylamines, e.g.
• alkyl-di-lower alkylamines e.g. N,N-dimethylamino- or N,N-diethylamino- ethanol
• amino sugars such as those in which the amino group is optionally substituted by at least one lower alkyl group, e.g.
• D-glucosamine, D-galactosamine or marmosamine derived from monosaccharides in which an alcoholic hydroxy group is replaced by an amino group
• N-methyl-D-glucosamine an N-lower alkylated amino sugar
• cycloalkylamines such as mono- or di-cycloalkylamines, e.g. cyclohexylamine or dicyclohexylamine, basic amino acids, e.g. arginine, histidine, lysine or ornithine, or cyclic amines, such as lower alkyleneamines or lower alkenyleneamines, e.g.
• pyrrolidine 1-ethyl-pyrrolidine, 2-hydroxyethyl-pyrrolidine, piperidine, 1-ethyl-piperidine, 2-hydroxyethyl- piperidine or pyrroline, or lower alkyleneamines or lower alkenyleneamines in which the carbon chain is interrupted by aza (-NH-), N-lower alkylaza [-N(-lower alkyl)-], oxa (-O-) and/or thia (-S-), e.g. imidazoline, 3-methylimidazoline, piperazine, 4-methyl- or 4- ethylpiperazine, morpholine or thiomorpholine.
• Preferred antihistaminic compounds are acrivastine, brompheniramine, chlorpheniramine.. dexchlorpheniramine, dimethindene, triprolidine; bromodiphenhydramine, clemastine, phenyltoloxamine, piprinhydrinate, pyrilamine, tripelennamine, cetirizine, hydroxyzine; methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, loratadine, astemizole, diphenhydramine, levocabastine and terfenadine, or topically acceptable salts thereof.
• antihistaminic compounds are dimethindene and clemastine, or a topically acceptable salt thereof, e.g. dimethindene maleate or clemastine hydrogen fumarate.
• a terpenoid compound is, for example, a monoterpenoid compound, a diterpenoid compound, a triterpenoid compound or a sesquiterpenoid compound.
• a monoterpenoid compound is e.g. camphor, 3-carene, carvacrol, carvone, chrysanthemic acid; cineol, e.g. 1 ,8-cineol; gefarnate, geraniol, linalool, limonene, menthol, pulegone, thujone or thymol.
• a diterpenoid compound is e.g. aphidicolin, forskolin, phytanic acid or phytol.
• a triterpenoid compound is, for example, glycyrrhetinic acid or a sapogenin, e.g. oleanolic acid or diosgenin.
• a sesquiterpenoid compound is e.g. farnesol or santonin.
• terpenoid compound is intended also to cover any derivative and any topically acceptable salt of a terpenoid compound.
• a carboxylic acid is, for example, a C C 7 -aliphatic, a cycloaliphatic, an aromatic, an aromatic-C ⁇ -C 7 -aliphatic, a heteroaromatic or a heteroaromatic-C ⁇ -C 7 -aliphatic carboxylic acid, which carboxylic acid may be unsubstituted or substituted, for example by one or more substituents selected from hydroxy, halogen, C- * -C 7 -alkoxy, carboxy, C ⁇ -C 7 -alkoxycarbonyl, cyano, amino, CrC 7 -alkylamino, di-CrC-r-alkylamino, C ⁇ -C 7 -alkanoylamino, nitro, C ⁇ -C 7 -alkyl and halogen-C C 7 -alkyl (e.g.trifluoromethyl).
• substituents selected from hydroxy, halogen, C- * -C 7 -alkoxy, carboxy,
• a carboxylic acid is a C 1 -C 7 - alkanoic acid which is unsubstituted or substituted by hydroxy, halogen, carboxy or amino, a C 3 -C 7 -cycloalkanoic acid; a phenyl-C,-C 7 -alkanoic acid, a benzoic acid or a naphthoic acid in each of which the phenyl ring(s) may be unsubstituted or substituted by one or more substituents selected from d-C 7 -alkyl, halogen-CrC -alkyl, hydroxy, halogen, CrC 7 -alkoxy, carboxy, C C 7 -alkoxycarbonyl, cyano, amino, C ⁇ -C 7 -alkylamino, di-d-C-V-alkylamino, C ⁇ -C - alkanoylamino and nitro; or a heteroaromatic carboxylic acid or a
• a carboxylic acid is a d-C 7 -alkanoic acid which is unsubstituted or substituted by hydroxy.
• Preferred terpenoid compounds are menthol, menthol esters, especially menthyl lactate, or cineol, more preferably menthol or menthyl lactate, and in one embodiment menthol, and in another embodiment menthyl lactate.
• menthyl lactate The structural formula of menthyl lactate is as follows:
• racemate As the compound contains 4 asymmetric carbon atoms, there are existing 16 different stereoisomers.
• the term “menthyl lactate” is intended to cover each of these stereoisomers as well as any racemates and any other mixtures of these stereoisomers. Preferred is the racemate of the following structure
• the combination according to the invention can be applied, usually in the form of a topical pharmaceutical composition, to any portion of the skin.
• application to the external genitalia, or the eyelids, or lips is not suggested, recommended, or usually desired.
• a topical pharmaceutical composition for topical administration the antiallergic and anti inflammatory efficacy of the combination is enhanced in an unexpected manner.
• the antihistaminic compound and the terpenoid compound both act as topical antiinflammatory agents but have different mechanisms of action and therefore act complementarily.
• the topical compositions of the invention are characterised by an extremely good skin permeation of the drugs applied.
• the topical pharmaceutical compositions of the invention have valuable pharmacological properties. Especially they are beneficial in the treatment of allergic and inflammatory skin diseases including atopic dermatitis.
• compositions of the invention are confirmed by classical toxicological studies, such as the acute toxicity mice test, the acute rabbit skin/eye irritation test or sensitization tests. Adverse effects, such as rough skin or skin irritation, are not observed.
• the invention relates to the use of a mixture of an antihistaminic compound with a terpenoid compound, in which mixture the antihistaminic compound is present in an amount of from 0.01 up to 15%, and the terpenoid compound is present in an amount of from 0.1 up to 15%, especially of from 0.1 up to 10%, very especially of from 0.5 up to 10%, more especially of from 0.5 up to 8%, most especially of from 1 up to 8%, advantageously of from 2 up to 8%, in particular of from 3 up to 8%, and first and foremost of from 4 up to 8%; further of from 3 up to 10%.
• the combination of an antihistaminic compound and a terpenoid compound is used in the form of a topical pharmaceutical composition which is also an object of the present invention.
• the invention further relates to a topical pharmaceutical composition
• a topical pharmaceutical composition comprising at least one topically applicable antihistaminic compound and at least one terpenoid compound together with at least one topically acceptable carrier material.
• the topically administered pharmaceutical compositions according to the invention comprise both the topically applicable antihistaminic compound(s) and the terpenoid compound in pharmacologically effective amounts.
• the daily dosage of the active ingredients depends on age and individual condition and on the mode of administration.
• the topical pharmaceutical compositions for example in the form of emulsion-gels, creams or ointments, may be applied once, twice or three times daily. But also more frequent daily applications are possible: such can provide a continual therapy which may lead to an even more rapid improvement of the conditions treated..
• Patches and bandages may be applied, for example, once daily or only once, twice or three times a week.
• a topical composition of the invention - as well in a mixture used according to the invention - the antihistaminic compound(s) is (are) e.g. present in an amount of from 0.01 up to 15%, especially of from 0.02 up to 5%, and in particular of from 0.02 up to 2.5%, of the total composition.
• the terpenoid compound is present in an amount of from 0.1 up to 15%, especially of from 0.1 up to 10%, very especially of from 0.5 up to 10%, more especially of from 0.5 up to 8%, most especially of from 1 up to 8%, advantageously of from 2 up to 8%, in particular of from 3 up to 8%, and first and foremost of from 4 up to 8%; further of from 3 up to 10%.
• the dosage of the active ingredients may depend on various factors, such as warmblooded species, sex, age, weight and individual condition of the warm-blooded animal.
• the invention relates to a method of treating allergic and inflammatory skin diseases which comprises topically administering to a mammal in need of such treatment a therapeutically effective amount of at least one antihistaminic compound together with a therapeutically effective amount of at least one terpenoid compound.
• compositions suitable for topical administration are e.g. creams, lotions, ointments, microemulsions, fatty ointments, gels, emulsion-gels, pastes, foams, tinctures, solutions, patches, bandages and transdermal therapeutic systems; preferred are emulsion- gels, gels, creams, lotions, solutions, patches and bandages.
• Creams or lotions are oil-in-water emulsions.
• oily base there are used especially fatty alcohols, especially those containing from 12 to 18 carbon atoms, for example lauryl, cetyl or stearyl alcohol, fatty acids, especially those containing from 10 to 18 carbon atoms, for example palmitic or stearic acid, fatty acid esters, e.g. glyceryl tricaprilocaprate (neutral oil) or cetyl palmitate, liquid to solid waxes, for example isopropyl myristate, wool wax or beeswax, and/or hydrocarbons, especially liquid, semi-solid or solid substances or mixtures thereof, for example petroleum jelly (petrolatum) or paraffin oil.
• fatty alcohols especially those containing from 12 to 18 carbon atoms, for example lauryl, cetyl or stearyl alcohol
• fatty acids especially those containing from 10 to 18 carbon atoms, for example palmitic or stearic acid
• Suitable emulsifiers are surface-active substances having predominantly hydrophilic properties, such as corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols and/or ethylene oxide adducts thereof, especially corresponding fatty acid esters with (poly)ethylene glycol, (poly)propylene glycol or sorbitol, the fatty acid moiety containing especially from 10 to 18 carbon atoms, especially partial glycerol fatty acid esters or partial fatty acid esters of polyhydroxyethylene sorbitan, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), and also polyoxyethylene fatty alcohol ethers or fatty acid esters, the fatty alcohol moiety containing especially from 12 to 18 carbon atoms and the fatty acid moiety especially from 10 to 18 carbon atoms, such as polyhydroxyethylenecetylstearyl ether (for example Cetomacrogol 1000) or polyhydroxy- ethyleneg
• Additives to the aqueous phase are, inter alia, agents that prevent the creams from drying out, for example humectants, such as polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and also preservatives, perfumes, gelling agents, etc..
• humectants such as polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and also preservatives, perfumes, gelling agents, etc.
• Ointments are water-in-oil emulsions that contain up to 70%, but preferably from approximately 20% to approximately 50%, water or aqueous phase.
• Suitable as fatty phase are especially hydrocarbons, for example petroleum jelly, paraffin oil and/or hard paraffins, which, in order to improve the water-binding capacity, preferably contain suitable hydroxy compounds, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols, or wool wax or beeswax.
• Emulsifiers are corresponding lipophilic substances, for example of the type indicated above, such as sorbitan fatty acid esters (Spans), for example sorbitan oleate and/or sorbitan isostearate.
• Additives to the aqueous phase are, inter alia, humectants, such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, and also preservatives, perfumes, etc.
• humectants such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, and also preservatives, perfumes, etc.
• Microemulsions are isotropic systems based on the following four components: water, a surfactant, for example a tensioactive, a lipid, such as a non-polar or polar oil, for example paraffin oil, and an alcohol or polyalcohol containing lipophilic groups, for example 2- octyldodecanol or ethoxalated glycerol or polyglycerol esters.
• a surfactant for example a tensioactive
• a lipid such as a non-polar or polar oil, for example paraffin oil
• an alcohol or polyalcohol containing lipophilic groups for example 2- octyldodecanol or ethoxalated glycerol or polyglycerol esters.
• other additives may be added to the microemulsions.
• Fatty ointments are water-free and contain as base especially hydrocarbons, for example paraffin, petroleum jelly and/or liquid paraffins, also natural or partially synthetic fat, such as fatty acid esters of glycerol, for example coconut fatty acid triglyceride, or preferably hardened oils, for example hydrogenated groundnut oil, castor oil or waxes, also fatty acid partial esters of glycerol, for example glycerol mono- and di-stearate, and also, for example, the fatty alcohols increasing the water-absorption capacity, emulsifiers and/or additives mentioned in connection with the ointments.
• hydrocarbons for example paraffin, petroleum jelly and/or liquid paraffins
• natural or partially synthetic fat such as fatty acid esters of glycerol, for example coconut fatty acid triglyceride, or preferably hardened oils, for example hydrogenated groundnut oil, castor oil or waxes, also fatty acid partial esters of glycerol,
• aqueous gels water-free gels and gels having a low water content, which gels consist of swellable, gel-forming materials.
• gels consist of swellable, gel-forming materials.
• transparent hydrogels based on inorganic or organic macromolecules.
• High molecular weight inorganic components having gel-forming properties are predominantly water-containing silicates, such as aluminium silicates, for example bentonite, magnesium aluminium silicates, for example Veegum, or colloidal silicic acid, for example Aerosil.
• high molecular weight organic substances there are used, for example, natural, semi- synthetic or synthetic macromolecules.
• Natural and semi-synthetic polymers are derived, for example, from polysaccharides containing a great variety of carbohydrate components, such as celluloses, starches, tragacanth, gum arabic and agar-agar, and gelatin, alginic acid and salts thereof, for example sodium alginate, and derivatives thereof, such as lower alkylcelluloses, for example methyl- or ethyl-cellulose, carboxy- or hydroxy-lower alkylcelluloses, for example carboxymethyl-or hydroxyethyl-cellulose.
• the components of synthetic gel-forming macromolecules are, for example, suitably substituted unsaturated aliphatic compounds such as vinyl alcohol, vinylpyrrolidine, acrylic or methacrylic acid.
• polymers examples include polyvinyl alcohol derivatives, such as polyviol, polyvinylpyrrolidines, such as collidone, polyacrylates and polymethacrylates, especially having a molecular weight of from approximately 80000 to approximately 1 million, or salts thereof, such as Rohagit S, Eudispert or Carbopol (Carbomer).
• Customary additives such as preservatives, humectants or perfumes, may be added to the gels.
• Emulsion-gels - also called “emulgels” - represent topical compositions which combine the properties of a gel with those of an oil-in-water emulsion. In contrast to gels, they contain a lipid phase which due to its fat-restoring properties enables the formulation to be massaged in whilst, at the same time, the direct absorption into the skin is experienced as a pleasant property. Furthermore, one can observe an increased solubility for lipophilic active ingredients.
• One advantage of emulsion-gels over oil-in-water emulsions resides in the enhanced cooling effect which is brought about by the coldness due to evaporation of the additional alcohol component, if present. Furthermore, one can observe an improved solubility of polar active ingredients.
• Foams are administered, for example, from pressurised containers and are liquid oil-in- water emulsions in aerosol form; unsubstituted hydrocarbons, such as alkanes, for example propane and/or butane, are used as propellant.
• hydrocarbons for example paraffin oil, fatty alcohols, for example cetyl alcohol, fatty acid esters, for example isopropyl myristate, and/or other waxes.
• emulsifiers there are used, inter alia, mixtures of emulsifiers having predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and emulsifiers having predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans).
• Teweens polyoxyethylene sorbitan fatty acid esters
• Spans sorbitan fatty acid esters
• the customary additives such as preservatives, etc., are also added.
• Tinctures and solutions generally have an ethanolic base, to which water may be added and to which there are added, inter alia, polyalcohols, for example glycerol, glycols and/or polyethylene glycol, as humectants for reducing evaporation, and fat-restoring substances, such as fatty acid esters with low molecular weight polyethylene glycols, propylene glycol or glycerol, that is to say lipophilic substances that are soluble in the aqueous mixture, as a replacement for the fatty substances removed from the skin by the ethanol, and, if necessary, other adjuncts and additives.
• Suitable tinctures or solutions may also be applied in spray form by means of suitable devices.
• Transdermal therapeutic systems with - in particular - local delivery of the active substances contain an effective amount of each of the active ingredients optionally together with a carrier:
• Useful carriers comprise absorbable pharmacological suitable solvents to assist passage of the active ingredients through the skin.
• the matrix (b) is normally present as a mixture of all components or may consist of separate layers.
• topically administrable pharmaceutical preparations are effected in a manner known p_er se, for example by dissolving or suspending the active ingredients in the base or, if necessary, in a portion thereof.
• active ingredients are administered in the form of a solution, they are generally dissolved in one of the two phases before emulsification.
• Example 1 An emulsion-gel containing the maleate salt of dimethindene and menthyl lactate is manufactured as follows.
• the acrylic acid polymerisate is dispersed in a portion of water by means of a rotor-stator homogeniser (for example Homorex*).
• a rotor-stator homogeniser for example Homorex*.
• a solution of the maleate salt of dimethindene, diethylamine, sodium sulphite and polyethylene glycol 300 in isopropanol and the remaining water is added thereto and distributed homogeneously.
• To form the fatty phase the polyhydroxyethylene cetyl stearyl ether, Mygliol* 812 and the paraffin oil are melted together at 75°. Menthyl lactate is added to the fatty phase, and then the whole fatty phase is slowly added to the previously formed gel and emulsified.
• Example 2 An emulsion-gel containing the maleate salt of dimethindene and menthyl lactate is manufactured as follows.
• the acrylic acid polymerisate is dispersed in a portion of water by means of a rotor-stator homogeniser (for example Homorex ® ).
• a rotor-stator homogeniser for example Homorex ®
• a solution of dimethindene maleate, NaOH, butylhydroxytoluene, disodium edetate and benzalkonium chloride in a mixture of propylene glycol/water is added thereto and distributed homogeneously.
• the polyhydroxyethylene cetyl stearyl ether, Mygliol* 812, the paraffin oil and benzyl alcohol are melted together at 75°.
• the menthyl lactate is added to the fatty phase, and then the whole fatty phase is slowly added to the previously formed gel and emulsified.
• Example 3 An emulsion-gel containing the maleate salt of dimethindene and l-menthol has the following composition and is manufactured in analogy to the examples 1 and 2.
• Example 4 A lotion containing the maleate salt of dimethindene and menthyl lactate has the following composition and is manufactured in analogy to the examples 1 and 2.
• Example 5 An emulsion-gel containing clemastine hydrogen fumarate and menthyl lactate is manufactured as follows.
• the acrylic acid polymerisate is dispersed in a portion of water by means of a rotor-stator homogeniser (for example Homorex*).
• a rotor-stator homogeniser for example Homorex*.
• a solution of clemastine hydrogen fumarate, diethylamine, sodium sulphite and polyethylene glycol 300 in isopropanol and the remaining water is added thereto and distributed homogeneously.
• the polyhydroxyethylene cetyl stearyl ether, Mygliol* 812 and the paraffin oil are melted together at 75°. Menthyl lactate is added to the fatty phase, and then the whole fatty phase is slowly added to the previously formed gel and emulsified.

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• 1997
  • 1997-07-01 EP EP97930461A patent/EP0910410A1/en not_active Withdrawn
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  • 1997-07-01 WO PCT/EP1997/003421 patent/WO1998000168A1/en not_active Application Discontinuation
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