WO2011076401A1

WO2011076401A1 - Substantially water-free pharmaceutical compositions containing acetylsalicylic acid

Info

Publication number: WO2011076401A1
Application number: PCT/EP2010/007863
Authority: WO
Inventors: Holger Schankin
Original assignee: Holger Schankin
Priority date: 2009-12-23
Filing date: 2010-12-22
Publication date: 2011-06-30

Abstract

The invention relates to a substantially water-free 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_2-4-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 substituents (component (D)), and optionally one or more further physiologically acceptable auxiliary agents as further component(s).

Description

Acetylsalicylic acid-containing, substantially anhydrous pharmaceutical

compositions

The present invention relates to 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 (ASA) 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.

However, in the presence of water, aspirin may be cleaved into salicylic acid and acetic acid due to insufficient hydrolysis stability of ASA, leading to a substantial loss of pharmacological activity

CONFIRMATION COPY of ASS. This hydrolysis reaction can also by

Heat are accelerated.

In the prior art known semi-solid or liquid dosage forms of acetylsalicylic acid therefore usually show insufficient hydrolysis stability, especially over a longer period. 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. Usually, such solid, ASA-containing administration forms are administered orally.

However, 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%. In addition, the released breakdown product salicylic acid can lead to gastrointestinal side effects such. lead to serious stomach bleeding.

In addition, it has long been known that the galenic processing of

Active substance ASS, especially in solid dosage forms, often too

various condensation products of acetylsalicylic acid, e.g.

Acetylsalicylic anhydride leads, what u.a. also leads to a reduction in the pharmacological activity of ASA.

There is therefore a need for ASA-containing pharmaceutical

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.

This object is achieved by the provision of the invention, in

Substantially anhydrous pharmaceutical composition comprising a combination of components (A) to (D):

(A) acetylsalicylic acid or a physiologically acceptable salt or a physiologically acceptable ester thereof,

(B) at least one C2-4 aliphatic monohydric alcohol,

(C) at least one at least dihydric alcohol,

(D) at least one compound selected from the group consisting of sugar substitutes and sugar substitutes, and optionally one or more further physiologically acceptable excipients as further component (s), dissolved.

An object of the present invention is therefore a substantially anhydrous pharmaceutical composition comprising a combination of components (A) to (D):

(B) at least one C 1-4 aliphatic monohydric alcohol, (C) at least one at least dihydric alcohol,

(D) at least one compound selected from the group consisting of sugar substitutes and sugar substitutes, and optionally one or more further physiologically compatible excipients as further component (s)

Surprisingly, it has now been found that 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.

For the purposes of this invention, 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. ,

For the purposes of this invention, 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.

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.

The term 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 salts of acetylsalicylic acid are preferably, but also salts with basic compounds such as ammonium salts [NH _n R _4-n] ^+, wherein n = 0, and 1, 2, 3 or 4 R is a branched or unbranched Cie-alkyl radical or salts with protonated or C _1-8 -alkylated amino acids, preferably lysine or arginine.

The term 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

Carboxyl function of acetylsalicylic acid with a optionally substituted with at least one NH ₂ - substituted C _1-8 alkanol, preferably esterified with an optionally substituted with at least one NH ₂ group d-4-alkanol. 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.

Preferably, 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.

In another preferred embodiment, 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

Composition.

As component (B) at least one C _2-4 aliphatic monohydric alcohol is present in the composition according to the invention.

The term "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. Preferably, 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. Most preferably, substantially anhydrous, is ethanol, i. purest ethanol with an ethanol content of at least 99.5%, preferably of at least 99.8%.

Preferably, 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.

In another preferred embodiment, 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.

As component (C) 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. Optionally, a carbon atom of these aliphatic and cycloaliphatic radicals may be replaced by the grouping -O-C (= O) -. Aliphatic hydrocarbon radicals may be branched or unbranched. In addition to dihydric alcohols, i. However, alkanediols and cycloalkanediols are also polyhydric alcohols (polyols) having more than two OH functions, i. e.g. trivalent, tetravalent or pentavalent alcohols in which three, four or five different carbon atoms each carry an OH function as an alcohol group, from this term. 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-ιο- 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

Carbon atoms as chain members, so are at least divalent C2-24 aliphatic alcohols. Preference is given to at least divalent C 1-4 -aliphatic alcohols having 2 to 8 carbon atoms as chain members. 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). If 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).

Preferably, 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.

In another preferred embodiment, 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.

In another preferred embodiment of the invention

Composition are the components (B) and (C) in a relative

Weight ratio of 5: 1 to 1: 5, preferably from 3: 1 to 1: 3, more preferably from 2: 1 to 1: 2, most preferably from 1, 5: 1 to 1: 1, 5,

in particular of 1: 1 in the composition according to the invention.

The components (B) and (C) are preferably used as solvents for the

Component (A) of the composition according to the invention. As 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.

Preferably, 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. In contrast, sugar substitutes have a sweetening power of the order of sucrose or less. Sugar substitutes are e.g. Sugar alcohols and fructose.

Preferably, 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.

Preferably, the sugar substitute is selected from the group consisting of xylitol, lactitol, sorbitol, isosorbitol, mannitol, isomalt, maltitol, fructose and their physiologically acceptable salts.

The term physiologically acceptable salts of the above-mentioned sugar substitutes and sugar substitutes is understood in the sense of this

Salts which are physiologically compatible - especially when used in humans and / or mammals. Physiologically acceptable salts of

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. A very particularly preferred sugar substitute as

Component (D) is saccharin which is not in the form of any of its physiologically acceptable salts, i. Saccharin in salt-free form.

Preferably, 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.

In another preferred embodiment, 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.

Preferably, 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.

In another preferred embodiment of the invention

Composition are the components (A) and (D) in a relative

Weight ratio of 10: 1 to 1: 1, preferably from 8: 1 to 1: 1, more preferably from 5: 1 to 1: 1, most preferably from 2: 1 to 1: 1, in particular from 1, 5: 1 to 1: 1 in the composition according to the invention.

In a preferred embodiment, the inventive

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,

(B) at least one C ^ -aliphatic, monohydric alcohol, preferably selected from the group consisting of ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol, in an amount of 10 to 40 Wt .-%, preferably from 15 to 35 wt .-%, each based on the total weight of the composition,

(C) at least one at least dihydric alcohol, preferably

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

(1, 2,3-propanetriol), in an amount of 10 to 40 wt .-%, preferably from 15 to 35 wt .-%, each based on the total weight of the composition,

(D) at least one compound selected from the group consisting of sugar substitutes and sugar substitutes, preferably selected from the group consisting of saccharin, aspartame, cyclamate, thaumatin, acesulfame, dulcine, miraculin, suosan, stevioside (stevia), xylitol, lactitol, sorbitol, Isosorbitol, mannitol, isomalt, maltitol, fructose and their physiologically tolerated salts, more preferably at least one sugar substitute, in an amount of from 0.1 to 5.5% by weight, preferably from 0.2 to 5.0% by weight , each on the

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

Add composition to 100 wt .-%.

In a preferred embodiment of the composition according to the invention, at least one compound of the general formula (I) is present as a further physiologically compatible excipient as component (E)

(I). where k is 0 or 1, preferably 1,

R ^{1 is} H, a Ci _-8 -aliphatic radical or a C (= 0) -Ci. ₈ - aliphatic radical is, and

R ^{2 is} a Ci _-8- aliphatic radical or a C (= 0) -Ci-8-aliphatic radical.

Component (E) is preferably used as further solvent component for component (A) of the composition according to the invention.

The term "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. Preferably, 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.

Preferably component (E) is selected from the group consisting of diethylene glycol monoethyl ether, diethylene glycol diethyl ether,

Diethylene glycol monomethyl ether, diethylene glycol dimethyl ether,

Diethylene glycol methyl ethyl ether, diethylene glycol methyl ether acetate,

Diethylene glycol ethyl ether acetate ethylene glycol monoethyl ether,

Ethylene glycol monomethyl ether, ethylene glycol diethyl ether,

Ethylene glycol dimethyl ether, ethylene glycol methyl ether acetate,

Ethylenglykolethyletheractetat. Particularly preferred

Diethylene.

Preferably, 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.

In another preferred embodiment, 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

Composition.

In a preferred embodiment of the composition according to the invention, at least one fatty alcohol is present as another physiologically acceptable excipient as component (F).

The expression "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

preferably monovalent C ₇ -35 alkanols, C _7- 35-alkenols and C _7- 35-alkynols. 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)

(II). wherein 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.

Particularly preferably 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. 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 and 2-decyl, and wherein 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, tetradecyl,

Pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, henicosyl, docosyl, tricosyl and tetracosyl. Most preferably, component (F) is selected from the group consisting of cetyl alcohol, cetylstearyl alcohol, stearyl alcohol and 2-octyldocecanol. Particularly preferred is 2-octyldocecanol.

Preferably, 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.

In another preferred embodiment, 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.

In a further preferred embodiment of the invention

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.

Preferably 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 oleates, more preferred

Polyoxyethylene sorbitan monooleates, polyethylene glycols and polyethylene glycol derivatives. Preferred polyethylene glycols have the general formula (IV)

H- (O-CH ₂ CH ₂ ) i -OH (IV) wherein

I is 4 to 1000, preferably 100 to 800, particularly preferably 200 to 600.

Preferred polyethylene glycol derivatives have the general formula (V) HO-R ⁵ -C (= O) - (O-CH ₂ CH ₂ ) m -OR ⁶ (V), where m is 4 to 1000, preferably 100 to 800, more preferably 200 to 600, and R ⁵ is (CH ₂₎ i _-30, preferably (CH ₂₎ _4-25, more preferably (CH ₂₎ 8- ₂ o, stands, and

R ^{6 is} CH ₂ - (CHOH) -CH ₂ OH.

A particularly preferred component (G) is selected from the group consisting of polyethylene glycols of the general formula (IV) with I = 200 to 600 and polyethylene glycol derivatives of the general formula (V) with m = 200 to 600. A particularly preferred component (G) is

Polyethylene glycol glycerol hydroxystearate (Macrogol glycerol hydroxystearate).

Preferably, the component (G) is in the inventive

In another preferred embodiment, 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.

In a particularly preferred embodiment, the composition according to the invention comprises a combination of components (A) to (G):

(A) Acetylsalicylic acid or a physiologically acceptable salt or a physiologically acceptable ester thereof, preferably

(B) at least one C2-4 aliphatic monohydric alcohol, preferably selected from the group consisting of ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol, more preferably ethanol, in one Amount of 10 to 40 wt .-%, preferably from 15 to 35 wt .-%, each based on the total weight of the composition,

(C) at least one at least dihydric alcohol, preferably

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,

(E) at least one compound of the general formula (I) in which k is 0 or 1, preferably 1,

R ^{1 is} H, a Ci _-8 -aliphatic radical or a

aliphatic radical is, and

R ² for a Ci. ₈ -aliphatic radical or a C (= 0) -Ci-8 aliphatic radical, in an amount of 5 to 20 wt .-%, preferably from 7 to 19% by weight, each based on the total weight of the composition .

(F) at least one fatty alcohol of the general formula (II) wherein

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,

(G) at least one nonionic solubilizer selected from the group consisting of sorbitan esters, preferably sorbitan stearates, more preferably sorbitan monostearates,

Polyoxyethylene sorbitan ester, preferably

Polyoxyethylene sorbitan oleates, more preferred

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).

In a further preferred embodiment of the invention

Composition is present as another physiologically acceptable excipient as component (H) at least one cyclic oligosaccharide.

Preferably, 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

Composition.

As component (H) there is preferably at least one cyclic oligosaccharide selected from the group consisting of α-, β- and γ-cyclodextrins whose OH functions may be esterified or etherified, i.

may preferably be substituted by a C (= O) -Ci _-8 -aliphatic or de-aliphatic radical, wherein the Ci-s-aliphatic radical may optionally in each case in turn be substituted by at least one OH group.

The term includes "Ci _-8 -aliphatic radical" (H) in connection with the component in the sense of this invention 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. Preferably, 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. Particularly preferred α-, β- and γ-cyclodextrins as component (H) are methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, acetyl-β-cyclodextrin, diacetyl-β-cyclodextrin, triacetyl-β-cyclodextrin, acetyl-a Cyclodextrin, diacetyl-a-cyclodextrin, triacetyl-a-cyclodextrin, acetyl-y-cyclodextrin, diacetyl-y-cyclodextrin and triacetyl-γ-cyclodextrin. Very particular preference is given to hydroxypropyl-.beta.-cyclodextrin.

Preferably, 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.

In another preferred embodiment, 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.

In a further preferred embodiment of the invention

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),

Pandanus oil (Pandanus odoratissimus) containing phenylethyl methyl ether, Fagara oil (Szechuan pepper, Callophyllum inophyllum lam.), Nutmeg oil (Myristica fragrans), soybean oil, olive oil, coconut oil, sesame oil, almond oil and whale oil. Very particularly preferred component (I) is anethole-containing essential oil from Ravensara anisata. Preferably, 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.

In another preferred embodiment, 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.

In a further preferred embodiment of the invention

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,

Mannose, gulose, idose, talose, psicose, fructose, sorbose, tagatose, fucose, sucrose (sucrose), lactose, maltose, trehalose, chitin or cellobiose.

In a further preferred embodiment of the invention

Composition apart from ASA at least one other physiologically acceptable and pharmacologically active ingredient as component (K) before. Preferably, 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. In a further preferred embodiment of the composition according to the invention, 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, α- and γ-linolenic acid, omega-3 fatty acids, caproic acid, caprylic acid, lauric acid, myristic acid, palmitic acid and stearic acid.

In a further preferred embodiment of the invention

Composition is present as a further physiologically acceptable excipient as component (M) at least one fatty acid ester. The term "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. For the purposes of the present invention, 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.

In a further preferred embodiment of the invention

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. Preferably, as component (N) is butyl adipate.

In a further preferred embodiment of the invention

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.

In a further preferred embodiment of the invention

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

(Lecithin), phosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyeline, dipalmitoylphosphatidylcholine (DPPC),

Dimyristoylphosphatidylglycerol (DMPG), cardiolipin, lysophosphatidylethanolamines, lysophosphatidylcholines, gangliosides, ceramides, cerebrosides, methacrylate lipids, thiol and disulphide lipids, and 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.

As component (P) is a mixture of DPPC and DMPG in the

According to the invention 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. Particularly preferred is a relative weight ratio of DPPC to DMPG in the

Composition of at least 25: 1, preferably of at least 15: 1, more preferably of at least 10: 1.

In a further preferred embodiment of the invention

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

Benzyl alcohol, transdermal uptake promoters, preferably dimethyl sulfoxide or tetrahydrofuran, permeation enhancer, preferably selected from the group of cyclic terpenes, more preferably selected from the group consisting of L-menthol, thymol and cineole, mucopolysaccharides, preferably acemannan, proteins, preferably bovine serum albumin (BSA )

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,

Potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, chelating agents, preferably selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA) and diethylenetriamine pentaacetic acid (DTPA), keratolytics, preferably selected from the group consisting of urea, salicylic acid,

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).

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. In particular, for example, the component (A) of the components (B), (C) and (D) and optionally other components may be present separately. However, 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.

The pharmaceutical compositions of the invention appear toxicologically harmless and are therefore suitable as a medical device or

Drug.

The pharmaceutical compositions of the invention are suitable for administration to adults and children, including infants and

Infants and can be used as liquid, pasty, semi-solid or solid pharmaceutical forms (dosage forms), for example in the form of solutions, e.g. Injection and infusion solutions, micellar solutions, drops, juices, syrups, sprays,

Suspensions, tablets, patches, ie patches, capsules, suppositories, dispersions, ointments, creams, lotions, pastes, fluidosomes, liposomes, nanosomes, ointments, gels, emulsions, preferably nanoemulsions and microemulsions, aerosols or in multiparticulate form, for example in the form of Pellets or granules, optionally compressed into tablets, filled into capsules or suspended in a liquid, are present and administered as such.

Furthermore, preferred drug forms are patches, i. Transdermal or sustained release transdermal patch systems, also called transdermal

therapeutic systems (TTS) referred to the specialist as matrix or

Membrane patches are known in which the inventive pharmaceutical

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.

The construction of 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,

WO92 / 20343, WO 92/20343, WO 00/76315 and Mäder, Karsten; Weidenauer, Uwe; Innovative dosage forms. A textbook for study and practice. 2010

Scientific publishing company Stuttgart. Chapter 18, pages 301-321:

Transdermal Therapeutic Systems (ISBN: 978-3-8047-2455-6).

Preferred pharmaceutical forms of the pharmaceutical according to the invention

Compositions are liquid or semi-solid formulations which are characterized by being stable formulations in terms of the content of ASA.

Particularly preferred liquid pharmaceutical forms are solutions, dispersions, suspensions and emulsion. In a very particularly preferred embodiment, 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). In another particularly preferred embodiment is the

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. In a very particularly preferred embodiment, 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).

If the 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).

In a very particularly preferred embodiment, 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).

As 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.

Preferably, 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. In this context, the term "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,

Methylcellulose, methylethylcellulose, etc. Particularly preferred is 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.

In another preferred embodiment, 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.

The 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.

The choice of the other physiologically acceptable excipients including components (E) to (Q) and the amounts thereof to be used depends on whether the pharmaceutical compositions according to the invention are administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, topically, by inhalation, intradermally, intramuscularly, intranasally , buccal, rectal or transdermal. For 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. However, a topical application is particularly preferred. For these are preferably solutions, suspensions, emulsions,

Dispersions, ointments, creams, lotions, pastes, fluidosomes, ointments, gels and more preferably solutions and gels, most preferably gels, in particular in the form of a roll-on system, as a spray or packaged as a tube or in the form of a topical patch system.

Particularly preferred is also a transdermal application. For these are 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.

The pharmaceutical compositions according to the invention, in particular in the form of a solution or a gel, 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.

The pharmaceuticals of the invention are preferably suitable

Compositions for the treatment and / or prophylaxis of one or more diseases selected from the group consisting of muscle pain, joint pain, osteoarthrosis, injuries after sports injuries, migraine, pain of the mouth and throat, e.g. Sore throat, acne,

Insect bites, insect bites, psoriasis, neurodermatitis, atopic dermatitis, eczema, contact dermatitis, thermal or chemical burns,

Sunburn, pruritus and acute herpetic neuralgia. Acetylsalicylic acid (ASA) is known to be almost exclusively administered by oral administration in antithrombotic therapy for the prevention of

Platelet aggregation used. The antithrombotic effect of ASA occurs through the irreversible inhibition of thromboxane A2 biosynthesis, which is an advantage over other non-steroidal anti-inflammatory drugs whose action is reversible. 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

Prevention of myocardial infarction, stroke, for the treatment of unstable angina pectoris and for thrombosis prophylaxis after use of vascular prostheses (stents) or artificial heart valves, cerebral blood circulation and

Thrombosis prophylaxis of the peripheral arterial vessels and for the treatment of atherosclerotic arterial diseases.

The pharmaceuticals of the invention are preferably suitable

Therefore, 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

Thrombosis prophylaxis of the peripheral arterial vessels and for the treatment of atherosclerotic arterial diseases, particularly preferred for the inhibition of platelet aggregation.

The suitability of ASA for antithrombotic therapy is known, for example, from WO2006 / 010748, US 2006/0189584, US 2006/0217352, WO 01/03774 and WO 03/041743.

The 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

Antiplatelet therapy.

The pharmaceutical compositions of the invention are also applicable to transdermal administration. The advantage of a transdermal

Administration is in close control of the drug release rate.

The permeability of ASA by the human skin and thus its fundamental suitability as a component of medicated skin plasters is basically known.

Another object of the present invention are also transdermal

Systems (TTS), e.g. in the form of 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.

Particularly preferred are the pharmaceutical according to the invention

Compositions therefore for the treatment and / or prophylaxis of one or more diseases selected from the group consisting of

Muscle pain, osteoarthritis and trauma after sports injuries.

Another object of the invention relates to 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). Preferably, 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, in particular the amount of component (A), 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,

Body weight of the patient of component (A) of the invention

applied to pharmaceutical composition.

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

Pharmaceutical jars, 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

Polyterephthalates (PET), polyvinyl acetates (PVA) and cyclic olefin homopolymers or copolymers (COC), 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

Preparation of the pharmaceutical compositions of the invention. Preferably, the pharmaceutical according to the invention

Compositions e.g. in the form of solutions or gels, essentially manufactured and stored under exclusion of air and moisture.

The production methods used for this purpose are known to the person skilled in the art.

The method for producing the pharmaceutical compositions according to the invention preferably comprises the steps if appropriate (a) dissolving component (H) in component (B),

(B) mixing the optionally component (H) contained component (B) with

Component (C),

(c) dissolving component (A) in the mixture of components

(B) and (C) and optionally (H),

(d) dissolving component (D) in the mixture of components (A), (B),

(C) and if necessary (H),

if necessary, (e) dissolving component (Q) in the mixture of components (A), (B),

(C), (D) and optionally (H), optionally with heating of the mixture, optionally (f) addition of at least one of the components (E), (F), (G), (I) to

(P) and optionally at least one further physiologically acceptable

Excipient to the mixture of components (A), (B), (C), (D), and optionally (H) and / or (Q), optionally with heating of the mixture.

Determination of ASA content (stability studies)

The stability of 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.).

In contrast to usual stability studies in which the amount of the hydrolysis product of ASA, i. is determined by salicylic acid, the above-mentioned method is characterized in that it is more accurate, since other degradation products are considered as salicylic acid.

The HPLC system used to determine the ASA content of the individual samples comprised a pump from Agilent (Pump series 1100), a

Autosampler from Perkin Elmer (Perkin Elmer series 200) and a UV detector from Agilent (Agilent DAD series 1 100, wavelength 234 nm). The chromatographic separation (injection volume: 20 μΙ) was carried out on an analytical column from Phenomenex (150 x 4.6 mmm Luna® 5 μιη C18, Part 00F-4041-EO) with an upstream precolumn from Phenomenex (4 x 4 mmm Luna ® C18) at a flow rate of 1 ml / min. The mobile phase MB _gel was a 70:30 mixture of mobile phase A (MB _A ) and mobile phase B (MB _B ). As 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

(Initial value), determined after one month and after six months by HPLC analysis. The following examples and comparative examples serve to illustrate the invention, but are not to be construed as limiting.

I. Examples - Gel Formulations:

All subsequent% data are each wt%.

Example B1 - Gel Formulation A

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. Subsequently, with gentle stirring, 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

Diethylene glycol monoethyl ether (4.50 g) is mixed together to give mixture B. The mixture B is stirred into the mixture A drop by drop. The resulting mixture is then further stirred until complete swelling of the gel. The gel formulation A thus obtained has the following

Composition:

Example B2 - Gel Formulation B

Hydroxypropyl β-cyclodextrin (1.50 g) is completely dissolved in ethanol (7.65 g) and to this solution is added propylene glycol (7.65 g). Acetylsalicylic acid (ASS) (1.50 g) is added to this mixture with gentle stirring and until the complete solution of ASA. Subsequently, with gentle stirring, saccharin (0.75 g) is added and finally hydroxypropyl cellulose (0.75 g). The result is mixture A. Macrogol glycerol hydroxystearate (3.00 g), 2-octyldodecanol (2.70 g) and diethylene glycol monoethyl ether (4.50 g) are mixed together to give mixture B. The mixture B is stirred into the mixture A drop by drop. The resulting mixture is then further stirred until complete swelling of the gel. The gel formulation B thus obtained has the following composition:

Example B3 - Gel Formulation C

Hydroxypropyl β-cyclodextrin (3.00 g) is completely dissolved in ethanol (7.13 g) and to this solution is added propylene glycol (7.13 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 (0.30 g) is added first, followed by hydroxypropyl cellulose (0.75 g). The result is mixture A. Macrogol glycerol hydroxystearate (3.00 g), 2-octyldodecanol (2.70 g) and diethylene glycol monoethyl ether (4.50 g) are mixed together to give mixture B. The mixture B is stirred into the mixture A drop by drop. The resulting mixture is then further stirred until complete swelling of the gel. The gel formulation C thus obtained has the following composition: Components quantity

Acetylsalicylic acid (ASA) 5%

Propylene glycol 23.75%

Ethanol (99.8%) 23.75%

Saccharin (sodium-free) 1%

Hydroxypropyl-3-cyclodextrin 10%

Macrogol glycerol hydroxystearate 10%

2-octyldodecanol 9%

Diethylene glycol monoethyl ether 15%

Hydroxypropyl cellulose (HPC) 2.5%

Example B4 - Gel Formulation D

Hydroxypropyl β-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, followed by hydroxypropyl cellulose (0.75 g). The result is mixture A. Macrogol glycerol hydroxystearate (3.00 g), 2-octyldodecanol (2.70 g) and diethylene glycol monoethyl ether (4.50 g) are mixed together to give mixture B. The mixture B is stirred into the mixture A drop by drop. The resulting mixture is then further stirred until complete swelling of the gel. The gel formulation D thus obtained has the following composition:

Components quantity

Acetylsalicylic acid (ASA) 5%

Propylene glycol 23%

Ethanol (99.8%) 23%

Saccharin (sodium-free) 2.5%

Hydroxypropyl-β-cyclodextrin 10%

Macrogol glycerol hydroxystearate 10%

2-octyldodecanol 9%

Diethylene glycol monoethyl ether 15%

Hydroxypropyl cellulose (HPC) 2.5% Example B5 - Gel Formulation E

Hydroxypropyl β-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

Hydroxypropylmethylcellulose (HPMC) (0.75 g). The result is the mixture A, which is heated to 70 ° C until the HPMC has completely dissolved. Macrogol glycerol hydroxystearate (3.00 g), 2-octyldodecanol (2.70 g) and

Diethylene glycol monoethyl ether (4.50 g) is mixed together to give mixture 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 further stirred with cooling to room temperature until complete swelling of the gel. The gel formulation E thus obtained has the following composition:

Example B6 - Gel Formulation F

Hydroxypropyl β-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, followed by hydroxypropyl cellulose (0.60 g). This results in the mixture A. Macrogol glycerol hydroxystearate (2.40 g), 2-octyldodecanol (2.70 g), diethylene glycol monoethyl ether (4.50 g) and the essential oil Ravensara anisata (0.75 g) are added together to give mixture B mixed. The mixture B is stirred into the mixture A drop by drop. The resulting mixture is then further stirred until complete swelling of the gel. The gel formulation F thus obtained has the following composition:

Example B7 - Gel formulation G

Hydroxypropylmethylcellulose (HPMC) (0.60 g). 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

Room temperature continued until complete swelling of the gel. The gel formulation E thus obtained has the following composition: Components quantity

Acetylsalicylic acid (ASA) 5%

Propylene glycol 23%

Ethanol (99.8%) 23%

Saccharin (sodium-free) 2.5%

Hydroxypropyl-β-cyclodextrin 10%

Macrogol glycerol hydroxystearate 8%

2-octyldodecanol 9%

Diethylene glycol monoethyl ether 15%

Ravensara anisata (essential oil) 2.5%

Hydroxypropylmethylcellulose (HPMC) 2.0%

II. Comparative Example - Gel Formulation:

All subsequent% data are each wt%. Comparative Example C1 - Gel Formulation H

Hydroxypropyl β-cyclodextrin (3.00 g) is completely dissolved in ethanol (7.28 g) and to this solution is added propylene glycol (7.28 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, hydroxypropyl cellulose (0.75 g) is added. The result is the mixture A. Macrogol glycerol hydroxystearate (3.00 g), 2-octyldodecanol (2.70 g) and

Diethylene glycol monoethyl ether (4.50 g) is mixed together to give mixture B. The mixture B is stirred into the mixture A drop by drop. The resulting mixture is then further stirred until complete swelling of the gel. The gel formulation H thus obtained has the following

Composition: Components quantity

Acetylsalicylic acid (ASA) 5%

Propylene glycol 24.25%

Ethanol (99.8%) 24.25%

Hydroxypropyl-β-cyclodextrin 10%

Macrogol glycerol hydroxystearate 10%

2-octyldodecanol 9%

Diethylene glycol monoethyl ether 15%

Hydroxypropyl cellulose (HPC) 2.5%

Gel Formulation H contains no component (D). III. Examples - stable solutions: Example B8 - Formulation I

Hydroxypropyl β-cyclodextrin (2.50 g) is completely dissolved in ethanol (5.76 g) and to this solution is added propylene glycol (5.75 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. Subsequently, saccharin (0.63 g) is added with gentle stirring. The result is mixture A. Macrogol glycerol hydroxystearate (2.50 g), 2-octyldodecanol (2.25 g),

Diethylene glycol monoethyl ether (3.76 g) and the Ravensara anisata essential oil (0.64 g) are mixed together to give the B mixture. The mixture B is stirred into the mixture A. The formulation I thus obtained has the following composition:

Components quantity

Acetylsalicylic acid (ASA) 5%

Propylene glycol 23%

Ethanol (99.8%) 23%

Saccharin (sodium-free) 2.5%

Hydroxypropyl-β-cyclodextrin 10%

Macrogol glycerol hydroxystearate 10%

2-octyldodecanol 9%

Ravensara anisata (essential oil) 2.5%

Diethylene glycol monoethyl ether 15% Example B9 - Formulation J

Hydroxypropyl β-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. Subsequently, 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),

Diethylene glycol monoethyl ether (3.75 g), sodium oleate (0.75 g) and the essential oil Ravensara anisata (0.75 g) are mixed together to give mixture B. The mixture B is stirred into the mixture A. The formulation J thus obtained has the following composition:

Components quantity

Acetylsalicylic acid (ASA) 5%

Propylene glycol 21, 5%

Ethanol (99.8%) 21, 5%

Saccharin (sodium-free) 5%

Hydroxypropyl-β-cyclodextrin 10%

Macrogol glycerol hydroxystearate 10%

2-octyldodecanol 6%

Sodium oleate 3%

Ravensara anisata (essential oil) 3%

Diethylene glycol monoethyl ether 15%

III. Stability tests (determination of ASA content)

From samples of gel formulations A to H (Examples B1 to B7 and

Comparative Example C1) and of samples of Formulations I and J (stable

Solutions; B8 and B9), the stability of acetylsalicylic acid over its content in the formulations was determined according to the method described above over a period of six months.

The results of the stability studies are shown in Table 1.

Table 1.

^* nb = not determined

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%.

Claims

claims:

1. A substantially anhydrous pharmaceutical composition

comprising a combination of components (A) to (D):

(B) at least one C 1-4 aliphatic monohydric alcohol,

(C) at least one at least dihydric alcohol,

(D) at least one compound selected from the group consisting of sugar substitutes and sugar substitutes, and optionally one or more other physiologically acceptable excipients as further component (s).

2. A composition according to claim 1, characterized in that component (A) is present in an amount of 1 to 10 wt .-%, based on the total weight of the composition.

3. A composition according to any one of the preceding claims, characterized in that the components (B) and (C) each independently in an amount of 10 to 40 wt .-%, based on the

Total weight of the composition, are present.

4. A composition according to any one of the preceding claims, characterized in that component (D) is present in an amount of 0.1 to 5.5% by weight, based on the total weight of the composition.

5. A composition according to any one of the preceding claims, characterized in that as component (D) at least one compound selected from the group consisting of saccharin, aspartame, cyclamate, thaumatin, acesulfame, dulcine, miraculin, suosan, stevioside (stevia), xylitol , Lactitol, sorbitol, isosorbitol, mannitol, isomalt, maltitol, fructose and theirs

physiologically acceptable salts.

6. A composition according to any one of the preceding claims, characterized in that as a further physiologically acceptable excipient as component (E) at least one compound of general formula (I) is present

(I) wherein k is 0 or 1,

R ^{1 is} H, a C 1 -C 8 aliphatic radical or a C (= O) -Ci-8 aliphatic radical,

R ^{2 is} a Cie aliphatic radical or a C (= 0) -Ci-8 aliphatic radical.

7. A composition according to any one of the preceding claims, characterized in that as a further physiologically acceptable excipient at least one fatty alcohol (F) and / or at least one nonionic solubilizer (G) is present.

A composition according to any one of the preceding claims, characterized in that the composition is a combination of

Components (A) to (G) include:

(A) acetylsalicylic acid or a physiologically acceptable salt or a physiologically acceptable ester thereof in an amount of 2 to 8 wt .-%, each based on the total weight of

Composition, (B) at least one C 2- aliphatic monohydric alcohol in an amount of from 15 to 35% by weight, based in each case on the total weight of the composition,

(C) at least one at least divalent C _2-8 aliphatic alcohol in an amount of 15 to 35 wt .-%, each based on the

Total weight of the composition,

(D) at least one sugar substitute in an amount of 0.2 to 5.0

Wt .-%, each based on the total weight of

Composition,

(E) at least one compound of the general formula (I),

wherein k is 0 or 1, R ^{1 is} H, is a Ci-e-aliphatic radical or a C (= O) -Ci-8 aliphatic radical, and R ^{2 is} a Cie aliphatic radical or a C (= O) -Ci-8-aliphatic radical, in an amount of 5 to 20 wt .-%, each based on the

Total weight of the composition, at least one fatty alcohol of the general formula (II),

(II). wherein R ^{3 is} H and R ^{4 is} a C6-34 aliphatic radical, in an amount of 5 to 15 wt .-%, each based on the

Total weight of the composition,

(G) at least one nonionic solubilizer selected from the group consisting of sorbitan esters, polyoxyethylene sorbitan esters, polyethylene glycols and polyethylene glycol derivatives, in an amount of 5 to 15 wt .-%, each based on the total weight of the composition, and optionally one or several other physiologically acceptable excipients as further component (s).

9. A composition according to any one of the preceding claims, characterized in that it is liquid and in the form of a stable solution.

A composition according to any one of claims 1-8, characterized

in that it is semi-solid, in the form of a gel and comprises at least one gelling agent (Q).

11. A composition according to claim 10, characterized in that the gelling agent (Q) is selected from the group consisting of celluloses, cellulose ethers and cellulose esters.

12. A composition according to any one of the preceding claims, characterized in that at least one component of the other

Components are present separately.

A composition according to any one of the preceding claims for

topical application.

14. A composition according to any one of the preceding claims for the treatment and / or prophylaxis of one or more diseases selected from the group consisting of muscle pain,

Joint pain, osteoarthrosis, trauma after sports injuries, migraine, acne, insect bites, insect bites, psoriasis, neurodermatitis, atopic dermatitis, eczema, contact dermatitis, thermal or chemical

Burns, sunburn, pruritus and acute herpetic neuralgia.

15. A composition according to any one of the preceding claims

antithrombotic therapy, preferably for treatment and / or

Prophylaxis of one or more cardiovascular and cerebrovascular diseases, particularly preferably for the treatment and / or prophylaxis of myocardial infarction, stroke, for the treatment of unstable angina pectoris and thrombosis prophylaxis after use of vascular prostheses (stents) or artificial heart valves, cerebral blood circulation and for thrombosis prophylaxis peripheral arterial vessels or for the treatment of atherosclerotic arterial diseases, particularly preferably for the inhibition of platelet aggregation.

16. A process for producing a composition according to any one of

preceding claims, comprising the steps

(b) mixing component (B) with component (C),

(c) dissolving component (A) in the mixture of components

(B) and (C)

(d) dissolving component (D) in the mixture of components

(A), (B), (C)

optionally (e) dissolving component (Q) in the mixture of components

(A), (B), (C), (D), optionally with heating of the mixture,

optionally (f) addition of at least one of components (E), (F), (G),

and optionally at least one further physiologically acceptable excipient to the mixture of components (A), (B), (C), (D) and optionally (Q), optionally with heating of the mixture.

17. A transdermal therapeutic system comprising a composition according to any one of the preceding claims.