WO2011076401A1 - Compositions pharmaceutiques sensiblement exemptes d'eau, contenant de l'acide acétylsalicylique - Google Patents

Compositions pharmaceutiques sensiblement exemptes d'eau, contenant de l'acide acétylsalicylique Download PDF

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Publication number
WO2011076401A1
WO2011076401A1 PCT/EP2010/007863 EP2010007863W WO2011076401A1 WO 2011076401 A1 WO2011076401 A1 WO 2011076401A1 EP 2010007863 W EP2010007863 W EP 2010007863W WO 2011076401 A1 WO2011076401 A1 WO 2011076401A1
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component
composition
composition according
physiologically acceptable
mixture
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PCT/EP2010/007863
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German (de)
English (en)
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Holger Schankin
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Holger Schankin
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    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the present invention relates to a substantially anhydrous pharmaceutical composition
  • a substantially anhydrous pharmaceutical composition comprising a combination of the components
  • Acetylsalicylic acid or a physiologically acceptable salt or a physiologically acceptable ester thereof (component (A)), at least one C ⁇ -aliphatic, monohydric alcohol (component (B)), at least one at least dihydric alcohol (component (C)), at least one compound selected from the group consisting of sugar substitutes and sugar substitutes (component (D)), and optionally one or more other physiologically acceptable excipients as further component (s).
  • Acetylsalicylic acid is known as "Aspirin” and has long been used as an active ingredient against various medical indications. ASA is used, for example, as an analgesic, antipyretic, antiphlogistic. In addition, ASA is suitable for cardiac infarction prophylaxis, for the treatment of angina pectoris and for the prevention of ischemic strokes.
  • Acetylsalicylic acid with its acetylated phenol function, has an ester linkage which, although stable in a dry environment and in a crystalline form, is stable in the presence of the aspirin, but in a humid environment, e.g. in an aqueous solution is sensitive to hydrolysis.
  • Hydrous pharmaceutical compositions containing ASA as an active ingredient are described e.g. in WO 01/03774 A2, WO 03/041743 A1, DE 27 21 831 A1 and EP 0 784 975 A1.
  • EP 0 803 254 A1 describes alcoholic solutions containing ASA.
  • US Pat. No. 4,126,681 US Pat. No. 4,219,548 and EP 1 009 410 B1 disclose solutions of acetylsalicylic acid with anhydrous organic solvents.
  • EP 0 055 635 A1 discloses gel compositions containing ASA.
  • ASA is therefore usually applied in solid form, e.g. in the form of tablets, sustained-release capsules or as granules for ingestion.
  • Such solid dosage forms as e.g. Tablets are used e.g. in EP 0 140 203 A2.
  • Such solid, ASA-containing administration forms are administered orally.
  • the oral route of application has the above-mentioned disadvantages, as well as orally administered ASA is subject to rapid hydrolysis due to their insufficient hydrolysis stability.
  • the oral availability of ASA in solid tablet compositions is therefore only about 50%.
  • the released breakdown product salicylic acid can lead to gastrointestinal side effects such. lead to serious stomach bleeding.
  • Active substance ASS especially in solid dosage forms, often too
  • Acetylsalicylic anhydride leads, what u.a. also leads to a reduction in the pharmacological activity of ASA.
  • compositions which do not have the aforementioned disadvantages. It was therefore an object of the invention to provide new pharmaceutical compositions, in particular in semisolid or liquid administration form, in particular for topical application, which contain ASA as active ingredient and have advantages over prior art compositions. In particular, it was an object of the invention to provide ASS-containing pharmaceutical compositions in the form of a stable solution or a stable gel. This pharmaceutical
  • compositions should be distinguished in particular by a long-term stability of the acetylsalicylic acid contained in them against hydrolysis into their degradation products.
  • Substantially anhydrous pharmaceutical composition comprising a combination of components (A) to (D):
  • An object of the present invention is therefore a substantially anhydrous pharmaceutical composition
  • a substantially anhydrous pharmaceutical composition comprising a combination of components (A) to (D):
  • the pharmaceutical composition according to the invention in particular in semisolid or liquid dosage form such as in the form of a solution or a gel, characterized in that the component contained therein (A) over a longer period of 6 months, even at room temperature stable Hydrolysis in their
  • Degradation products i. especially in salicylic acid and acetic acid, and therefore there is no reduction in the pharmacological activity of the pharmaceutical composition, especially in topical application, even over a prolonged period of storage.
  • the term “stable” or “stability” means that the pharmaceutical composition according to the invention is distinguished by the fact that the component (A) contained therein is stable to hydrolysis in its degradation products over a period of 6 months, ie. especially stable to hydrolysis in salicylic acid and acetic acid. After a period of 6 months at room temperature, the pharmaceutical composition according to the invention preferably still contains at least 85%, more preferably at least 90%, most preferably at least 95%, in particular still at least 98% of the amount of component (A) initially contained therein. ,
  • the term "substantially anhydrous" means that the pharmaceutical composition according to the invention has a water content of at most 5% by weight, preferably of at most 2% by weight, particularly preferably of at most 0.5% by weight. -%, most preferably of at most 0.1 wt .-%, in particular of at most 0.05 wt .-%, particularly preferably of at least 0.01 wt .-%, each based on the
  • Total weight of the composition The determination of the water content can be carried out by customary methods known to the person skilled in the art, for example by Karl Fischer titration.
  • acetylsalicylic acid As the pharmacologically active component (A), acetylsalicylic acid (ASS) or a physiologically acceptable salt or a physiologically acceptable ester thereof is present in the composition according to the invention. It is clear to the person skilled in the art that acetylsalicylic acid is 2-acetoxybenzoic acid.
  • physiologically acceptable salts of acetylsalicylic acid in the context of this invention means salts which are physiologically acceptable, in particular when used in humans and / or mammals.
  • Physiologically acceptable salts of acetylsalicylic acid include salts with cations or bases in which acetylsalicylic acid is preferably present by deprotonation of the carboxyl function as anion with at least one inorganic or organic, preferably inorganic, cation, as counterion.
  • Particularly preferred are metal salts, most preferably the salts of the alkali and
  • Alkaline earth metals ie lithium, sodium, potassium, magnesium and calcium salts. Particular preference is given to (mono-) or (dis) sodium, (mono-) or (di) potassium, magnesium or calcium salts of acetylsalicylic acid.
  • physiologically acceptable ester of acetylsalicylic acid is to be understood in the sense of this invention as being preferably labile, i. Hydrolysis-sensitive esters of acetylsalicylic acid, which are physiologically compatible - especially when used in humans and / or mammals. It is the
  • Particularly preferred C 1-4 alkanols are C 1-4 alkanols selected from the group consisting of methanol, aminomethanol, ethanol, aminoethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol.
  • Acetylsalicylic acid (ASA) is preferably pharmacologically active
  • Component (A) in the composition according to the invention is Component (A) in the composition according to the invention.
  • the component (A) is in the inventive
  • Composition in an amount of 1 to 10 wt .-%, more preferably from 2 to 8 wt .-%, particularly preferably from 3 to 7 wt .-%, most preferably from 4 to 6 wt .-%, in particular of 4, 5 to 5.5 wt .-% before, in each case based on the total weight of the composition.
  • the component (A) in the composition according to the invention in an amount of at most 10 wt .-%, preferably of at most 8 wt .-%, more preferably of at most 7 wt .-%, most preferably of at most 6 wt .-%, in particular of at most 5.5 wt .-% before, in each case based on the total weight of
  • component (B) at least one C 2-4 aliphatic monohydric alcohol is present in the composition according to the invention.
  • C 2-4 aliphatic monohydric alcohol for the purposes of this invention includes acyclic, saturated, branched or unbranched, C 1-4 aliphatic hydrocarbon radicals of 2 to 4, i. 2, 3 or 4 carbon atoms, wherein a carbon atom carries an OH function as an alcohol group, i. monovalent C2-4 alkanols.
  • the C 2-4 aliphatic monohydric alcohol is selected from the group consisting of ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol and tert-butanol.
  • a particularly preferred C 1 -aliphatic, monohydric alcohol is ethanol.
  • substantially anhydrous is ethanol, i. purest ethanol with an ethanol content of at least 99.5%, preferably of at least 99.8%.
  • component (B) is in the invention
  • Composition in an amount of 10 to 40 wt .-%, more preferably from 15 to 35 wt .-%, particularly preferably from 18 to 32 wt .-%, most preferably from 20 to 30 wt .-%, in particular from 21 to 28 wt .-%, before, in each case based on the total weight of the composition.
  • component (B) is present in the composition according to the invention in an amount of at least 10% by weight, preferably at least 15% by weight, more preferably at least 18% by weight, most preferably at least 20 wt .-%, in particular of at least 21 wt .-%, particularly preferably of at least 23 wt .-% before.
  • At least one at least dihydric alcohol is present in the composition according to the invention.
  • the term "at least dihydric alcohol” for the purposes of this invention includes acyclic and cyclic, saturated hydrocarbon radicals, i. aliphatic and cycloaliphatic radicals, wherein at least two different carbon atoms of these radicals each carry an OH function as an alcohol group.
  • Aliphatic hydrocarbon radicals may be branched or unbranched.
  • alkanediols and cycloalkanediols are also polyhydric alcohols (polyols) having more than two OH functions, i.
  • Cycloaliphatic, at least dihydric alcohols preferably have 3 to 10, i. 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms as ring members, are therefore at least divalent C-3- ⁇ - cycloaliphatic alcohols.
  • Examples of at least divalent C 3-10 cycloaliphatic alcohols are sugar alcohols, preferably sorbitol or inositol.
  • Aliphatic, at least dihydric alcohols preferably have 2 to 24, i. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24
  • At least divalent C2-24 aliphatic alcohols are preferably selected from the group consisting of glycol (1, 2-ethanediol), 1, 2-propanediol (propylene glycol), 1, 3-popanediol, 1, 2 Butanediol, 1, 3-butanediol, 1, 4-butanediol, 2,3-butanediol, 1, 2-pentanediol and glycerol (1, 2,3-propanetriol).
  • an at least bivalent C2-24 aliphatic alcohol is at least simply esterified with an optionally OH-substituted fatty acid such as, for example, hydroxystearic acid, formally a carbon atom of the resulting at least divalent C 1-6 aliphatic alcohol is replaced by the
  • Ester bond formed group 0-C ( 0) replaced, such as in at least divalent C ⁇ - aliphatic alcohol propylene glycol hydroxystearate.
  • Aliphatic, preferably C 1-6 -aliphatic, at least dihydric alcohols are preferred as component (C) of the composition according to the invention.
  • Particularly preferred are aliphatic, preferably C 2-8 aliphatic, dihydric alcohols as component (C) of the composition according to the invention are very particularly preferred glycol, 1, 2-propanediol and 1, 3-propanediol. Particular preference is given to 1,2-propanediol (propylene glycol).
  • the component (C) is in the inventive
  • Composition in an amount of 10 to 40 wt .-%, more preferably from 15 to 35 wt .-%, particularly preferably from 18 to 32 wt .-%, most preferably from 20 to 30 wt .-%, in particular from 21 to 28 wt .-% before, in each case based on the total weight of the composition.
  • component (C) is present in the composition according to the invention in an amount of at least 10% by weight, preferably at least 15% by weight, more preferably at least 18% by weight, most preferably at least 20 wt .-%, in particular of at least 21 wt .-%, particularly preferably of at least 23 wt .-% before.
  • Composition are the components (B) and (C) in a relative
  • the components (B) and (C) are preferably used as solvents for the
  • Component (A) of the composition according to the invention Component (D) of the composition according to the invention.
  • component (D) at least one compound selected from the group consisting of sugar substitutes and sugar substitutes, preferably at least one sugar substitute, is present in the composition according to the invention.
  • component (D) effects stabilization in the
  • Composition of the invention contained component (A).
  • Sugar substitutes have a sweetening power that is significantly higher than the sweetening power of sucrose.
  • Sugar substitutes used according to the invention preferably have a sweetening power which is at least eight times as high as that of
  • Sucrose is.
  • sugar substitutes have a sweetening power of the order of sucrose or less.
  • Sugar substitutes are e.g. Sugar alcohols and fructose.
  • the sugar substitute is selected from the group consisting of saccharin, aspartame, cyclamate, thaumatin, acesulfame, dulcine, miraculin, suosan, stevioside (stevia) and their physiologically acceptable salts.
  • the sugar substitute is particularly preferably selected from the group consisting of saccharin, aspartame, cyclamate, thaumatin, acesulfame, stevia and their physiologically acceptable salts.
  • the sugar substitute is selected from the group consisting of xylitol, lactitol, sorbitol, isosorbitol, mannitol, isomalt, maltitol, fructose and their physiologically acceptable salts.
  • physiologically acceptable salts of the above-mentioned sugar substitutes and sugar substitutes is understood in the sense of this
  • Sugar substitutes and sugar substitutes include salts with cations, preferably inorganic or organic cations, or bases. Particularly preferred are metal salts and ammonium salts, most preferably the Salts of alkali and alkaline earth metals, ie lithium, sodium, potassium, magnesium and calcium salts.
  • a particularly preferred sugar substitute as component (D) is saccharin or its physiologically tolerated salts, in particular its sodium, potassium or calcium salts.
  • Component (D) is saccharin which is not in the form of any of its physiologically acceptable salts, i. Saccharin in salt-free form.
  • the component (D) is in the inventive
  • Composition in an amount of 0.1 to 5.5 wt .-%, more preferably from 0.2 to 5.0 wt .-%, particularly preferably from 0.5 to 4.5 wt .-%, most preferably from 0.7 to 4 wt .-%, in particular from 1 to 3 wt .-% before, in each case on the total weight of the composition.
  • component (D) in the composition according to the invention is present in an amount of at most 5.5% by weight, preferably of at most 5.0% by weight, particularly preferably of at most 4.5% by weight. , very particularly preferably of at most 4 wt .-%, in particular of at most 3 wt .-%, particularly preferably at most 2.5 wt .-% before, in each case based on the total weight of the composition.
  • component (A) is present in a higher amount of wt% than component (D) in the composition of the invention, based on the total weight of the composition.
  • Composition are the components (A) and (D) in a relative
  • Composition a combination of components (A) to (D): (A) Acetylsalicylic acid or a physiologically acceptable salt or a physiologically acceptable ester thereof, preferably
  • Acetylsalicylic acid in an amount of from 1 to 10% by weight, preferably from 2 to 8% by weight, based in each case on the total weight of the composition,
  • At least one at least divalent C 2-8 aliphatic alcohol selected from the group consisting of glycol (1, 2-ethanediol), 1, 2-propanediol (propylene glycol), 1, 3-popanediol, 1, 2-butanediol, 1, 3 Butanediol, 1, 4-butanediol, 2,3-butanediol, 1, 2-pentanediol and glycerol
  • composition Total weight of the composition, and optionally one or more other physiologically acceptable excipients as further component (s). All components of the composition according to the invention always add up to 100% by weight. If the components (A) to (D) of the composition according to the invention do not add to 100% by weight, the inventive composition comprises
  • composition one or more other physiologically acceptable excipients as another component (s), so that in total all components of
  • At least one compound of the general formula (I) is present as a further physiologically compatible excipient as component (E)
  • Component (E) is preferably used as further solvent component for component (A) of the composition according to the invention.
  • C 1-8 -aliphatic radical in connection with the component (E) for the purposes of this invention comprises acyclic, saturated, branched or
  • unbranched hydrocarbon radicals having 1 to 8 carbon atoms, ie, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms as chain members.
  • the d -8 aliphatic radical is selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, n-heptyl, n-octyl and includes. Particularly preferred are methyl and ethyl.
  • component (E) is selected from the group consisting of diethylene glycol monoethyl ether, diethylene glycol diethyl ether,
  • the component (E) is in the inventive
  • Composition in an amount of 5 to 20 wt .-%, more preferably 7 to 19 wt .-%, particularly preferably from 9 to 18 wt .-%, most preferably from 10 to 16 wt .-%, each based on the total weight the composition.
  • component (E) in the composition according to the invention is present in an amount of at least 5% by weight, preferably at least 7% by weight, more preferably at least 10% by weight, most preferably at least 12 wt .-%, in particular of at least 14 wt. Before, in each case based on the total weight of
  • At least one fatty alcohol is present as another physiologically acceptable excipient as component (F).
  • fatty alcohol in the context of this invention comprises acyclic, saturated or unsaturated, aliphatic hydrocarbon radicals which may be branched or unbranched, having 7 to 35 carbon atoms, ie 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 carbon atoms as chain members, wherein at least one, preferably exactly one carbon atom carries an OH function as an alcohol group, ie
  • a particularly preferred C 7-35 aliphatic radical is a C 1-5 aliphatic radical, where at least one, preferably exactly one, carbon atom of this radical carries an OH function as an alcohol group.
  • a particularly preferred fatty alcohol is a compound of the following general formula (II)
  • R 3 is H and R 4 is a preferably branched C6-34 aliphatic radical, ie a C ⁇ alkyl, C6-34 alkenyl or C6-34 alkynyl radical, preferably a C ⁇ -Alkyl radical, is.
  • R 4 is CHR 4a R 4b , wherein R 4a is a C3-io-aliphatic radical, ie a C3-io-alkyl, C3-io-alkenyl or Ca ⁇ o-alkynyl radical, preferably for a C3-io-alkyl radical, more preferably a C3-io-alkyl radical selected from the group consisting of 1-propyl, 2-propyl, 1-butyl, iso-butyl, sec-butyl, tert.
  • n-pentyl iso-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 1-heptyl, 2-heptyl, 1-octyl, 2-octyl, 1-nonyl.
  • R 4b is a C 3-2 4 -aliphatic radical, ie a C2-24-alkyl, C 3-2 4-alkenyl or C 3 -alkyl radical 24 alkynyl radical, preferably a C3-24-alkyl radical, particularly preferably a C 3 i 0 alkyl residue selected from the group consisting of 1-propyl, 2-propyl, 1-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 1-heptyl, 2-heptyl, 1-octyl, 2-octyl, 1-nonyl, 2-nonyl, 1-decyl, 2-decyl, undecyl, dodecyl, tridecyl, te
  • component (F) is selected from the group consisting of cetyl alcohol, cetylstearyl alcohol, stearyl alcohol and 2-octyldocecanol. Particularly preferred is 2-octyldocecanol.
  • the component (F) is in the inventive
  • Composition in an amount of 5 to 15 wt .-%, more preferably 6 to 14 wt .-%, particularly preferably from 7 to 13 wt .-%, most preferably from 8 to 12 wt .-%, each on the total weight the composition.
  • component (F) in the composition according to the invention is present in an amount of at most 15% by weight, preferably at most 14% by weight, more preferably at most 13% by weight, most preferably at most 12 wt .-%, in particular of at most 10 wt.% Before, in each case based on the total weight of
  • Composition is present as another physiologically acceptable excipient as component (G) at least one nonionic solubilizer.
  • the component (G) preferably serves as an emulsifier and preferably comprises nonionic surfactants.
  • Emulsifiers are preferably added in amounts such that they allow a uniform mixing of the components of the pharmaceutical composition according to the invention.
  • nonionic solubilizers are used as component (G) for the pharmaceutical composition, the glycerol esters,
  • Polyoxyethylene glycerol ethers polyglycerol fatty acid esters, glycerin fatty acid esters, sorbitan esters, preferably sorbitan stearates, more preferably
  • Sorbitan monostearates polyoxyethylene sorbitan esters, preferably
  • Polyoxyethylene sorbitan monooleates polyethylene glycols and polyethylene glycol derivatives.
  • Preferred polyethylene glycols have the general formula (IV)
  • I is 4 to 1000, preferably 100 to 800, particularly preferably 200 to 600.
  • R 6 is CH 2 - (CHOH) -CH 2 OH.
  • a particularly preferred component (G) is
  • Polyethylene glycol glycerol hydroxystearate (Macrogol glycerol hydroxystearate).
  • the component (G) is in the inventive
  • Composition in an amount of 5 to 15 wt .-%, more preferably 6 to 14 wt .-%, particularly preferably from 7 to 13 wt .-%, most preferably from 8 to 12 wt .-%, each on the total weight the composition.
  • component (G) in the composition according to the invention is present in an amount of at most 15% by weight, preferably at most 14% by weight, more preferably at most 13% by weight, most preferably at most 12 wt .-%, in particular of at most 10% by weight, based in each case on the total weight of the composition.
  • composition according to the invention comprises a combination of components (A) to (G):
  • Acetylsalicylic acid in an amount of from 1 to 10% by weight, preferably from 2 to 8% by weight, based in each case on the total weight of the composition,
  • At least one at least divalent C 1-6 aliphatic alcohol selected from the group consisting of glycol (1,2-ethanediol), 1,2-propanediol (propylene glycol), 1,3-popanediol, 1,2-butanediol, 1,3 - Butanediol, 1, 4-butanediol, 2,3-butanediol, 1, 2-pentanediol and glycerol (1, 2,3-propanetriol), more preferably propylene glycol, in an amount of 10 to 40 wt .-%, preferably from From 15 to 35% by weight, based in each case on the total weight of the composition,
  • (D) at least one sugar substitute preferably selected from the group consisting of saccharin, aspartame, cyclamate, thaumatin, acesulfame, stevia and their physiologically acceptable salts, more preferably saccharin or its physiologically acceptable salts, most preferably saccharin, in one Amount of 0.1 to 5.5 wt .-%, preferably from 0.2 to 5.0 wt .-%, each based on the total weight of the composition,
  • R 1 is H, a Ci -8 -aliphatic radical or a
  • R 3 is H and R 4 is a preferably branched Ce-3 - aliphatic radical, in an amount of 5 to 15 wt .-%, preferably from 6 to 14% by weight, each based on the total weight of the composition,
  • Polyoxyethylene sorbitan ester preferably
  • Polyoxyethylene sorbitan monooleate polyethylene glycols, preferably polyethylene glycols of the general formula (IV), and polyethylene glycol derivatives, preferably polyethylene glycol derivatives of the general formula (V), in an amount of 5 to 15 wt .-%, preferably of 6 to 14 wt .-%, each based on the total weight of the composition, and optionally one or more other physiologically acceptable excipients as another component (s).
  • Composition is present as another physiologically acceptable excipient as component (H) at least one cyclic oligosaccharide.
  • the component (H) effects an additional stabilization of the component (A) contained in the composition according to the invention and / or an additional stabilization of the pharmaceutical according to the invention
  • component (H) there is preferably at least one cyclic oligosaccharide selected from the group consisting of ⁇ -, ⁇ - and ⁇ -cyclodextrins whose OH functions may be esterified or etherified, i.
  • Ci-s-aliphatic radical may optionally in each case in turn be substituted by at least one OH group.
  • the Ci-e-aliphatic radical is selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso -Pentyl, neo-pentyl, n-hexyl, n-heptyl, n-octyl and includes. Particularly preferred are methyl and ethyl.
  • ⁇ -, ⁇ - and ⁇ -cyclodextrins as component (H) are methyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, acetyl- ⁇ -cyclodextrin, diacetyl- ⁇ -cyclodextrin, triacetyl- ⁇ -cyclodextrin, acetyl-a Cyclodextrin, diacetyl-a-cyclodextrin, triacetyl-a-cyclodextrin, acetyl-y-cyclodextrin, diacetyl-y-cyclodextrin and triacetyl- ⁇ -cyclodextrin.
  • Very particular preference is given to hydroxypropyl-.beta.-cyclodextrin.
  • component (H) is in the invention
  • Composition in an amount of 1 to 20 wt .-%, more preferably from 4 to 16 wt .-%, particularly preferably from 5 to 15 wt .-%, most preferably from 8 to 12 wt .-% before, each on the Total weight of the composition.
  • component (H) in the composition according to the invention is present in an amount of at most 20% by weight, preferably at most 15% by weight, more preferably at most 13% by weight, most preferably at most 1 1 wt .-%, in particular of at most 10 wt.% Before, in each case based on the total weight of
  • Composition is as another physiologically acceptable excipient as component (I) at least one oil, preferably a vegetable oil, which can be extracted from plants or parts of plants. Preferably lies as
  • Component (I) an essential oil.
  • Particularly preferred as component (I) is at least one oil selected from the group consisting of anethole-containing essential oil from Ravensara anisata, trans-anethol containing aniseed aniseed aniseed oil (Pimpinella anisum), trans-anethole-containing essential oil from the star anise (Illicum verum), fennel oil (sweet) (Foeniculum vulgare),
  • component (I) is anethole-containing essential oil from Ravensara anisata.
  • component (I) is in the invention
  • Composition in an amount of from 1 to 10% by weight, more preferably from 2 to 8% by weight, more preferably from 3 to 6% by weight, most preferably from 4 to 5% by weight before, each on the Total weight of the composition.
  • component (I) in the composition according to the invention is present in an amount of at most 10% by weight, preferably at most 8% by weight, more preferably at most 6% by weight, most preferably at most 5 wt .-%, in particular of at most 4 wt.% Before, in each case based on the total weight of
  • Composition is present as another physiologically acceptable excipient as component (J) at least one sugar.
  • Suitable sugars are mono-, di-, oligo- and / or polysaccharides, such as, for example, erythrose, threose, xylose, arabinose, galactose, raffinose, lyxose, ribose, allose, altrose, glucose,
  • Composition apart from ASA at least one other physiologically acceptable and pharmacologically active ingredient as component (K) before.
  • it is selected from the group comprising dexpanthenol, codeine phosphate, paracetamol, phenacetin, propyphenazone, butalbital, salicylamide, ethencamide, aluminum glycinate, basic magnesium carbonate, caffeine,
  • Phenobarbital, pentobarbital, cyclobarbital, benzylmandelate, ascorbic acid, thiamine, meprobamate, quinine, non-steroidal anti-inflammatory rheumatics preferably selected from the group consisting of ibuprofen, flurbiprofen, naproxen, ketoprofen, diclofenac, indometaein, metamizole, tiaprofenic acid, mefenamic acid, piroxicam, Tenoxicam, meloxicam and phenylbutazone and antiphlogistic agents, preferably selected from the group consisting of suprofen, cliprofen, cicloprofen and fenoprofen.
  • at least one fatty acid or at least one of them is present as another physiologically acceptable excipient as component (L)
  • physiologically acceptable salts before. Suitable physiologically acceptable salts are the same salts which have been mentioned above in connection with component (A) of the composition according to the invention.
  • the term "fatty acid” in the sense of this invention comprises acyclic, saturated and at least simple, possibly also multiple, e.g. di- or tri-unsaturated aliphatic carboxylic acids, which may be branched or unbranched, having from 7 to 35
  • Carbon atoms i. with 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34 or 35 carbon atoms as
  • Chain links i. C7-35 fatty acids, preferably C7-30 alkyl and C7-3o alkenyl fatty acids.
  • Particularly preferred fatty acids and their physiologically acceptable salts are oleic acid, oleates, myristoleic acid, palmitoleic acid, cetoleic acid, linoleic acid, ⁇ - and ⁇ -linolenic acid, omega-3 fatty acids, caproic acid, caprylic acid, lauric acid, myristic acid, palmitic acid and stearic acid.
  • Composition is present as a further physiologically acceptable excipient as component (M) at least one fatty acid ester.
  • fatty acid ester in the context of this invention comprises esters of a monohydric or polyhydric, ie for example a di-, tri-, tetra- or pentavalent alcohol, wherein at least one of the alcohol functions of such a polyhydric alcohol is esterified with one of the abovementioned fatty acids. If several alcohol functions of the polyhydric alcohol are esterified with fatty acids, these alcohol functions can each be esterified independently with different fatty acids.
  • Preferred polyhydric alcohols are ethylene glycol and glycerol (glycerol).
  • a glycerin fatty acid ester thus comprises monoglycerides, diglycerides and triglycerides such as glyceryl monooleate, glyceryl monostearate or capryl triglyceride.
  • Preferred monohydric alcohols are C 2-6 alkanols, for example ethanol, isopropanol, isobutanol, 1-pentanol and 1-hexanol.
  • Preferred fatty acid esters formed from monohydric alcohols are isopropyl myristate and isopropyl palmitate.
  • a "fatty acid ester” is also an ester of a mono- or polyvalent, ie, for example, a di-, tri-, tetra- or trivalent carboxylic acid such as adipic acid, succinic acid, glutaric acid or pimelic acid understood, wherein at least one of the carboxylic acid functions of such a polybasic carboxylic acid with a fatty alcohol, as already associated with
  • Component (F) of the composition according to the invention has been esterified.
  • Composition is as another physiologically acceptable excipient as component (N) at least one ester of a monovalent C2-6-alkanol, preferably ethanol, iso-propanol, iso-butanol, 1-pentanol or 1 -hexanol and a
  • diacid carboxylic acid e.g. Adipic acid, succinic acid, glutaric acid or pimelic acid.
  • component (N) is butyl adipate.
  • Composition is as another physiologically acceptable excipient as component (O) at least one terpene, preferably at least one triterpene or a monocyclic monoterpene, more preferably a terpene selected from the group consisting of squalanes, squalene and limonene.
  • component (O) at least one terpene, preferably at least one triterpene or a monocyclic monoterpene, more preferably a terpene selected from the group consisting of squalanes, squalene and limonene.
  • Composition is as another physiologically acceptable excipient as component (P) at least one phospholipid, preferably at least one natural or synthetic phospholipid, more preferably one
  • Phospholipid selected from the group consisting of phosphatidylcholine
  • DMPG Dimyristoylphosphatidylglycerol
  • cardiolipin lysophosphatidylethanolamines
  • lysophosphatidylcholines gangliosides
  • ceramides cerebrosides
  • methacrylate lipids thiol and disulphide lipids
  • polymerizable lipids particularly preferred component (P) is at least one phospholipid selected from the group consisting of dipalmitoylphosphatidylcholine (DPPC) and dimyristoylphosphatidylglycerol (DMPG), most preferably a mixture of DPPC and DMPG.
  • DPPC dipalmitoylphosphatidylcholine
  • DMPG dimyristoylphosphatidylglycerol
  • As component (P) is a mixture of DPPC and DMPG in the
  • composition so are DPPC and DMPG preferably in a relative weight ratio of 25: 1 to 1:25, preferably from 20: 1 to 1:20, more preferably from 15: 1 to 1:15, most preferably from 10: 1 to 1:10, in the inventive Composition before.
  • Composition is as another physiologically acceptable excipient, e.g. as carrier material, filler, solvent, diluent, colorant, preservative, disintegrants, lubricant, lubricant, aroma and binder, at least one further component selected from the group consisting of polycyclic alcohols, preferably cholesterol, olefin bases, preferably selected from the group consisting of white and yellow vaseline (petrolatum), lanolins, beeswax, thick and thin and hard paraffins, plastastasis, cetanol and wool wax alcohols, fragrances and flavorings, preferably
  • BSA bovine serum albumin
  • water-adsorbing substances preferably zeolites, more preferably selected from the group consisting of heulandite (klioptilolite), natrolite and thromsonite, calcined silicon, calcined aluminum, modified starch, inhibitors of ASA hydrolysis, preferably acetic anhydride, inorganic salts, preferably selected from the group consisting made of calcium carbonate,
  • Potassium carbonate sodium chloride, calcium acetate, sodium acetate, potassium acetate, potassium chloride, magnesium sulfate, sodium phosphate, sodium sulfate,
  • Lactic acid, mandelic acid and glycolic acid, preservative preferably selected from the group consisting of sodium benzoate, chlorobutanol, benzoic acid, phenylethyl alcohol and phenol, vitamins, preferably selected from the group consisting of vitamin A (retinol), vitamin E (tocopherol) and vitamin K (phylloquinone), ketones, preferably acetone, not with Water-miscible alkanes and cycloalkanes, preferably selected from the group consisting of propane, butane, pentane, hexane and cyclohexane, diethyltoluamide (DEET), glyceryl acetate (monoacetin), benzoyl peroxide, sulfur, da-tocophenyl-polyethylene glycol 1000 succinate (TPGS) , herbal extracts, preferably aloe vera and / or momordica charantia (bitter melon).
  • vitamins preferably selected from the group consist
  • Another object of the present invention is a composition according to the invention, in which at least one component of the other
  • Components are present separately.
  • the component (A) of the components (B), (C) and (D) and optionally other components may be present separately.
  • component (A) it is also possible, for example, for component (A) to be present together with one or more components, and for this combination to be present separately from the combination of the other components.
  • the separately present components can then be brought together in particular immediately before or during the administration.
  • compositions of the invention appear toxicologically harmless and are therefore suitable as a medical device or
  • compositions of the invention are suitable for administration to adults and children, including infants and
  • solutions e.g. Injection and infusion solutions, micellar solutions, drops, juices, syrups, sprays,
  • preferred drug forms are patches, i. Transdermal or sustained release transdermal patch systems, also called transdermal
  • TTS therapeutic systems
  • composition liquid or semi-solid, e.g. as a solution or gel, or directly before, during or after topical application, by mixing the active ingredient in solid form with the liquid or semisolid solvent within the patch, e.g. using a two or more chamber system, e.g. Shaking, kinking, pressing, etc., in the pharmaceutical according to the invention
  • Composition is transferred.
  • plasters or transdermal therapeutic systems is basically known to the person skilled in the art, for example from DE 42 41 128 A1, DE 199 49 202 A1, WO 00/76315, EP 0 617 623, WO 2005/084255, WO 97/04759,
  • compositions are liquid or semi-solid formulations which are characterized by being stable formulations in terms of the content of ASA.
  • liquid pharmaceutical forms are solutions, dispersions, suspensions and emulsion.
  • the pharmaceutical composition according to the invention is in the form of a stable solution comprising the components (A) to (D), preferably (A) to (G), particularly preferably (A) to (H).
  • the pharmaceutical composition according to the invention is in the form of a stable solution comprising the components (A) to (D), preferably (A) to (G), particularly preferably (A) to (H).
  • the pharmaceutical composition according to the invention is in the form of a stable solution comprising the components (A) to (D), preferably (A) to (G), particularly preferably (A) to (H).
  • the pharmaceutical composition according to the invention is in the form of a stable solution comprising the components (A) to (D), preferably (A) to (G), particularly preferably (A) to (H).
  • the pharmaceutical composition according to the invention is in the form of a stable solution comprising the components (A) to (D), preferably (A) to (G), particularly preferably (A)
  • inventive pharmaceutical composition in semisolid form before.
  • Particularly preferred semisolid drug forms of the pharmaceutical composition of the invention are ointments, creams, lotions and gels.
  • the pharmaceutical composition according to the invention is in the form of a stable gel comprising components (A) to (D), preferably (A) to (G), more preferably (A) to (H).
  • composition according to the invention is in the form of a gel, it preferably has a component (H) which preferably serves for additional stabilization of the pharmaceutical composition according to the invention.
  • the pharmaceutical composition according to the invention in the form of a gel preferably also comprises at least one gelling agent (Q).
  • the composition according to the invention is liquid and is in the form of a stable solution or it is semisolid and is in the form of a gel and comprises at least one gelling agent (Q).
  • gelling agent (Q) it is possible to use synthetic, natural and / or semi-synthetic polymers which are swellable in nonaqueous solvents and generally have hydrophilic properties.
  • the gelling agent (Q) has a temperature resistance of at least 50 ° C, more preferably at least 75 ° C, even more preferably at least 100 ° C, most preferably at least 125 ° C, and most preferably at least 150 ° C.
  • temperature resistance means that when the gelling agent (Q) is heated to the respective temperature for 10 minutes and cooled to room temperature, no significant changes in properties occur compared to a reference sample of the gelling agent (Q) which was not heated.
  • Preferred gelling agents (Q) are synthetic or semi-synthetic polymers, such as celluloses and their derivatives, preferably cellulose, cellulose ethers and
  • Cellulose esters such as, for example, hydroxyethylcellulose, hydroxypropylmethylcelluloses (HPMC), hydroxypropylcellulose (HPC),
  • Carboxymethylcellulose or its salts such as Na-carboxymethylcellulose,
  • the gelling agent (Q) selected from the group consisting of hydroxypropylmethylcelluloses (HPMC) and hydroxypropylcellulose (HPC).
  • the gelling agent (Q) in the composition according to the invention is preferably present in an amount of from 0.1 to 10% by weight, preferably from 0.5 to 8% by weight, particularly preferably from 0.7 to 6% by weight, most preferably from 1 to 5 wt .-%, in particular from 1, 5 to 4 wt .-% before, each based on the total weight of the composition.
  • the gelling agent (Q) in the composition according to the invention is present in an amount of at most 10% by weight, preferably at most 8% by weight, more preferably at most 6% by weight, most preferably at most 5 wt .-%, in particular of at most 4 wt .-%, particularly preferably of at most 3 wt .-% before, in each case based on the total weight of the composition.
  • composition according to the invention may optionally comprise at least one further gelling agent, preferably selected from the group consisting of polyvinyl alcohols, polyvinyl acetates, polyvinylpyrrolidones, preferably Kollidon 12 PF and / or Kollidon 17 PF, polyacrylic acids and polyacrylate derivatives (Carbopole), Gelantine, Aerosil, aluminum and Zinc stearates and sodium alginate, included.
  • at least one further gelling agent preferably selected from the group consisting of polyvinyl alcohols, polyvinyl acetates, polyvinylpyrrolidones, preferably Kollidon 12 PF and / or Kollidon 17 PF, polyacrylic acids and polyacrylate derivatives (Carbopole), Gelantine, Aerosil, aluminum and Zinc stearates and sodium alginate, included.
  • compositions according to the invention are administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, topically, by inhalation, intradermally, intramuscularly, intranasally , buccal, rectal or transdermal.
  • oral administration are preferably pharmaceutical according to the invention Compositions in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups.
  • Sprays are preferred for buccal and inhalative administration.
  • a topical application is particularly preferred.
  • transdermal application particularly preferred is also a transdermal application.
  • solutions preferably solutions, suspensions, emulsions, dispersions, ointments, creams, lotions, pastes, fluidosomes, ointments, gels in the form of matrix or membrane plaster systems and more preferably solutions and gels, most preferably gels.
  • compositions according to the invention are preferably characterized, after topical application, by a very good spreadability, i. through a very rapid penetration into the skin, out.
  • the pharmaceuticals of the invention are preferably suitable
  • compositions for topical application to intact skin, i. on skin without external injuries are provided.
  • the pharmaceuticals of the invention are preferably suitable
  • Insect bites insect bites, psoriasis, neurodermatitis, atopic dermatitis, eczema, contact dermatitis, thermal or chemical burns,
  • Acetylsalicylic acid is known to be almost exclusively administered by oral administration in antithrombotic therapy for the prevention of
  • ASS is therefore particularly suitable for the treatment and / or prophylaxis of one or more cardiovascular and
  • cerebrovascular diseases in particular for the treatment and / or
  • the pharmaceuticals of the invention are preferably suitable
  • compositions also for antithrombotic therapy i. for the treatment and / or prophylaxis of one or more cardiovascular and cerebrovascular diseases, in particular for the treatment and / or
  • ASA for antithrombotic therapy
  • ASA oral nature of the administration of ASA is unfavorable due to the short biological half-life of the active ingredient and the desire for the most constant possible administration. Platelet aggregation inhibition occurs exclusively via the
  • Acetylsalicylic acid, the hydrolysis product salicylic acid causes no
  • compositions of the invention are also applicable to transdermal administration.
  • Another object of the present invention are also transdermal
  • TTS sustained release transdermal systems of substantially anhydrous pharmaceutical ASS containing
  • compositions for antithrombotic therapy with the aim of setting constant and reproducible ASA blood levels.
  • TTS systems avoid the first-pass metabolism effect of oral administration and prevent the side effects known to be caused by ASA in the gastrointestinal system, such as, e.g. Stomach bleeding.
  • compositions therefore for the treatment and / or prophylaxis of one or more diseases selected from the group consisting of
  • Another object of the invention relates to a cosmetic composition
  • a cosmetic composition comprising a combination of components (A) to (D) and optionally one or more further physiologically acceptable excipients as further component (s), preferably at least one of components (E) to (G) , particularly preferably at least one of components (E) to (H).
  • the cosmetic composition of the care of the skin preferably by topical application.
  • the pharmaceutical compositions of the present invention are prepared by conventional means, devices, methods and methods known in the art, as described, for example, in "Remington's Pharmaceutical Sciences", published by AR Gennaro, 17th Ed., Mack Publishing Company, Easton, Pa, 1985, in particular in part 8, chapters 76 to 93. The corresponding description is hereby incorporated by reference and is considered part of the disclosure.
  • the amount of the respective components of the pharmaceutical compositions according to the invention to be administered to the patient may vary and depends, for example, on the weight or age of the patient as well as on the mode of administration, the indication and the severity of the disease. Usually 0.001 to 100 mg / kg, preferably 0.05 to 75 mg / kg, particularly preferably 0.05 to 50 mg / kg,
  • the pharmaceutical compositions of the invention are preferably packaged.
  • Preferred packaging means are tubes, preferably tubes made of metal, particularly preferably aluminum, colorless or colored
  • compositions preferably pharmaceutical jars, of glass types I, II III and IV, dispensable containers such as gel dispensers, packaging materials based on polymer materials, preferably plastic materials, preferably based on at least one polymer material selected from the group consisting of polyvinylidene chloride (PVC), polyethylenes ( PE), polypropylene (PP), polyester, preferably
  • PET Polyterephthalates
  • PVA polyvinyl acetates
  • COC cyclic olefin homopolymers or copolymers
  • coatings of sealing lacquers tube varnishes, silicone oils, Teflon and elastomers such as butyl, bromobutyl or chlorobutyl rubber,
  • Silicones specialty rubber, e.g. Nitrile rubber for oil closures, single or multi-layer films for suppositories, paving foils and sachets.
  • Another object of the present invention is a method for
  • compositions e.g. in the form of solutions or gels, essentially manufactured and stored under exclusion of air and moisture.
  • the method for producing the pharmaceutical compositions according to the invention preferably comprises the steps if appropriate (a) dissolving component (H) in component (B),
  • acetylsalicylic acid is determined directly by determining its content in the pharmaceutical compositions according to the invention by means of HPLC analysis over a period of six months at a storage temperature of 4 ° C. and at room temperature RT (RT corresponds to 20 to 25 ° C.).
  • HPLC system used to determine the ASA content of the individual samples comprised a pump from Agilent (Pump series 1100), a
  • MB A an aqueous potassium dihydrogen phosphate solution (20 mM) having a pH of 2.2 (adjusted by phosphoric acid) was used.
  • the MBA used was a mixture of acetonitrile and methanol (7: 1).
  • Samples of each pharmaceutical composition are each stored for a period of six months at the corresponding temperatures (at 4 ° C or at RT) and the content of acetylsalicylic acid on the day of preparation
  • a mixture of ethanol (8.40 g) and propylene glycol (8.40 g) is presented.
  • Acetylsalicylic acid (ASS) (1.50 g) is added to this mixture with gentle stirring and stirring is continued until complete dissolution of the ASA.
  • saccharin (0.75 g) is added and finally hydroxypropyl cellulose (0.75 g).
  • the result is the mixture A. macrogol glycerol hydroxystearate (3.00 g), 2-octyldodecanol (2.70 g) and
  • ASA Acetylsalicylic acid
  • HPC Hydroxypropyl cellulose
  • the gel formulation D thus obtained has the following composition:
  • ASA Acetylsalicylic acid
  • Hydroxypropyl ⁇ -cyclodextrin (3.00 g) is completely dissolved in ethanol (6.90 g) and to this solution is added propylene glycol (6.90 g).
  • Acetylsalicylic acid (ASS) (1.50 g) is added to this mixture with gentle stirring and stirring is continued until complete dissolution of the ASA. Subsequently, with gentle stirring, saccharin (0.75 g) is added first and finally
  • HPMC Hydroxypropylmethylcellulose
  • Hydroxypropyl ⁇ -cyclodextrin (3.00 g) is completely dissolved in ethanol (6.90 g) and to this solution is added propylene glycol (6.90 g).
  • Acetylsalicylic acid (ASS) (1.50 g) is added to this mixture with gentle stirring and stirring is continued until complete dissolution of the ASA. Subsequently, with gentle stirring, saccharin (0.75 g) is added first and finally
  • HPMC Hydroxypropylmethylcellulose (0.60 g).
  • HPMC Hydroxypropylmethylcellulose
  • the result is the mixture A, which is heated to 70 ° C until the HPMC has completely dissolved.
  • Macrogol glycerol hydroxystearate (2.40 g), 2-octyldodecanol (2.71 g), diethylene glycol monoethyl ether (4.50 g) and the Ravensara anisata essential oil (0.74 g) are mixed together to give Blend B.
  • the mixture B is stirred into the heated mixture A drop by drop, the temperature is then kept constant at 60 ° C. for a further 5 minutes and subsequently stirred at 40 ° C. for a further hour.
  • the resulting mixture is then cooled
  • the gel formulation E thus obtained has the following composition: Components quantity
  • ASA Acetylsalicylic acid
  • HPMC Hydroxypropylmethylcellulose
  • composition Components quantity
  • ASA Acetylsalicylic acid
  • HPC Hydroxypropyl cellulose
  • ASA Acetylsalicylic acid
  • hydroxypropyl ⁇ -cyclodextrin (2.50 g) is completely dissolved in ethanol (5.38 g) and to this solution is added propylene glycol (5.38 g).
  • Acetylsalicylic acid (ASA) (1.25 g) is added to this mixture with gentle stirring and stirring is continued until complete dissolution of the ASA.
  • saccharin (1.25 g) is added with gentle stirring.
  • the result is the mixture A. macrogol glycerol hydroxystearate (2.50 g), 2-octyldodecanol (1, 50 g),
  • ASA Acetylsalicylic acid
  • the percentage of ASA in each case refers to the amount of ASA present in the samples of the individual formulations in% by weight, based on the total sample, ie. here each to 5 wt .-% ASA, this initial value is set equal to 100%.

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Abstract

La présente invention concerne une composition pharmaceutique sensiblement exempte d'eau, comprenant une combinaison des composants suivants : de l'acide acétylsalicylique ou un sel physiologiquement acceptable ou un ester physiologiquement acceptable dudit acide (composant (A)); au moins un alcool monovalent aliphatique en C2-4 (composant (B)); au moins un alcool au moins bivalent (composant (C)); au moins un composé sélectionné dans le groupe constitué par les succédanés du sucre (composant (D)); et éventuellement un ou plusieurs autres composants sous la forme d'un ou de plusieurs autres adjuvants physiologiquement acceptables.
PCT/EP2010/007863 2009-12-23 2010-12-22 Compositions pharmaceutiques sensiblement exemptes d'eau, contenant de l'acide acétylsalicylique WO2011076401A1 (fr)

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WO2016102959A1 (fr) * 2014-12-23 2016-06-30 Innovate Pharmaceuticals Limited Composition de composé salicylate
IT201700090344A1 (it) * 2017-08-04 2019-02-04 Poli Md S R L Dispositivo medicale per il trattamento delle infezioni cutanee da hpv
WO2019025884A1 (fr) * 2017-08-04 2019-02-07 Poli Md S.R.L. Dispositif médical pour le traitement d'infections cutanées à pvh
EA039331B1 (ru) * 2018-06-21 2022-01-14 Поли Мд С.Р.Л. Композиция для лечения кожных инфекций, вызванных вирусом папилломы человека

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