IE50921B1

IE50921B1 - Pharmaceutical preparations for topical application which contain salts of alkanecarboxylic acids,novel carboxylic acid salts and the production thereof

Info

Publication number: IE50921B1
Application number: IE30481A
Authority: IE
Original assignee: Ciba Geigy Ag
Priority date: 1981-02-16
Filing date: 1981-02-16
Publication date: 1986-08-20
Also published as: IE50922B1

Description

The present invention relates to pharmaceutical preparations for topical application which contain salts of alkanecarboxylic acids and the production thereof.

The present invention provides pharmaceutical preparations for topical application which contain a compound of the formula R. 1\ *2 ^‘<0 (I) wherein R^ is a group of the formula 1\ » ./ \ (Ila) wherein X2 and X^ are hydrogen and X^ is 2,6-dichloroanilino and R2 is hydrogen, and each of Rp K4 and Rj independently is hydrogen or an aliphatic radical, or two of R^, R^ and R. together are a bivalent aliphatic radical, unsubetituted or substituted or interrupted by aza, oxa or thia, vith the proviso chat at least one of R^, Rj and Rj is different from hydrogen, and the additional proviso that, if R^ is hydrogen and is methyl, R^ is different from 2,3,4,5,6peutahydroxy-l-hexyl which is derived from S-glucamine, optionally in the form of an isomer, together vith conventional carriers and/or excipients for topical application.

Pharmaceutical preparations for topical application are to be understood as meaning in particular those in which the active ingredient is presenc in a form in which ic can he absorbed hy the skin, e.g. together vith conventional carriers and/or excipients for topical application.

An aliphatic radical R^, &4 or R$ is preferably a louer alkyl radical uhich is unsubscicuted or substituted by amino,a group of the formula nh®®ooc-c: or hydroxyl. Examples of such radicals are louer alkyl, amino-lower alkyl, hydroxyl-lower alkyl, or oligo-hydroxylower alkyl.

A bivalent aliphatic radical is e.g. 4- to 7-membered louer alkylene, whilst a bivalent aliphatic radical which is interrupted by optionally substituted aza, or by oxa or thia, is e.g. 4- to 7-membered 3-aza-, 3-oxa- or 3-thia-lower alkylene, in which aza can be substituted e.g. by lover alkyl.

Throughout this specification, the term lower” .employed to qualify organic radicals and compounds denotes preferably those containing up to and including 7, most preferably up to and including 4, carbon atoms.

X5 The general definitions employed within the scope of this specification have the following preferred meanings: Lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also comprises corresponding pentyl, hexyl or heptyl radicals.

Amino-lower alkyl is preferably aainooethyl, 2-aainoethyl, 3-aminopropyl or 4-aminobutyl.

Hydroxy-lower alkyl contains in particular a hydroxyl group and is e.g. hydroxymethyl, 2-hydrexymethyl, 2- or 3-hydroxypropyl or 2-, 3- or 4-hydroxybucyl.

Oligcr-hydroxy-louer alkyl contain» at least tuo hydroxyl groups and is e.g. 1,2-dihydroxyethyl, 2,3-di- or 1,2,3-trihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tctrahydroxypentyl and also di(hydroxymethyl)oethyl, tri(hydroxymethyl)methyl or 2-dihydroxy5 methyl)ethyl.

Lower alkylene having 4 to 7 members is preferably 1,4-butylene, 1,5-pencylene, 1,6-hexylene, and 1,7-heptylene. 3-Ata-, 3-oxa- or 3-thia-lower alkylene having 4 to 7 members is preferably 3-aza-, 3-N-lower alkyl-aza-, such as 3-N-methy1-aza-, and 3-oxa- or 3-thia-l,S-pentylene, as well as corresponding butylene, hexylene or heptylene.

Rl\ The compounds of the formula CH-COOH (Ilia) or the salts thereof, R2 are known. These compounds and their salts with bases are used, for example, as non-steroidal antiinflassaatory agents for treating in15 flaoatory conditions. The preparations containing these compounds are administered for the most part orally and also enterally or parenterally. Successful therapy by percutaneous administration, however, frequently fails when using compounds of the formula (Ilia), because penetration of a therapeutically effective amount of active ingredient through the skin into the affected tissue cannot be adequately ensured.

The present invention is based on the surprising observation that the compounds of the formula (I) possess excellent percutaneous penetration and absorbtion properties. 50821 In addition, tbe coepoundi of the formula I have marked .pri'-jpg.·»..· tory and analgesic properties. The anti-inflammatory activity can be demonstrated e.g. by the marked reduction in the swelling in rats' paws in the kaolin edema test in accordance with Helv. Physiol, Acta 25, 156 (1967), by rubbing e.g. a gel containing about 0.5 to Z of active ingredient into tbe backs of test animals from which the hair has been removed (see Arsneimittel-Forschung 27 (I), 1326, 1977). Further, tbe anti-inf laautory activity of the active ingredient, e.g. in the form of a gel having a concentration of about 0.5 to 5 Z, when applied topically,can be deduced from the inhibition of abscees formation induced by subcutaneous injection of carageen in rats (see Arzneimittel-Forscbung 27 (I), 1326, 1977).

Assays using compounds of the forntla I in the phenyl-p-bensoquinone writhing test (J. Pharmacol. Therap. 125, 237, 1959) in the dosage range from about 1.0 to 120 mg p.o. indicate a marked analgesic activity.

Accordingly, the compounds of the formula I are most suitable antiinflaamatory agents for percutaneous application and can also be used as analgesics.

Accordingly, the invention preferably provides pharmaceutical preparations for topical application which contain a compound of the formula 1, . wherein and R^ are as defined hereinbefore, each of R^, R^ and independently is hydrogen, s lower alkyl radical which is unsubstituted or substituted by amino, a group of the formula or hydroxyl, or two of R^, R^ and Rj are 4- to 7-membered lover alkylene or 4- to 7-membered lover alkylene which is interrupted by optionally lower alkyl-substituted aza, or by oxa or thia, with tbe proviso that at least one of Rj, R^ and Rj is different from hydrogen. 50821 These preparations comprise e.g. pharmaceutical preparations for topical application uhich contain a compound of Che formula I, uherein R^ and have the given meanings, each of Rj, R^ and R$ independently is hydrogen, louer alkyl, amino-loucr alkyl, louer alkyl substituted by a group of the formula ©O -ΝΗ^ ^OoC-Clf , hydroxy-louer alkyl, oligo-hydroxy-louer alkyl, or two of R„, R, and R, are 4- to 7-membered louer alkylene or 43 4 5 to 7-meobered louer alkylene uhich is interrupted by optionally H-lower alkylated aza, or by oxa or thia, uith the proviso that, if Rj is hydrogen and R^ is methyl, Rj is different from 2,3,5,6-pentahydro1-hexyl which is derived from ii-glucamine.

The invention relates especially to pharmaceutical preparations for topical application uhich contain a compound of the formula I, uherein R^ and R^ have the given meanings, each of Rj, R^ and Rj indepen15 dently is lower alkyl containing up to and including 4 carbon acorns, such as methyl or ethyl, or hydroxy-louer alkyl containing up to and including 4 carbon atoms, such an 2-hydroxyethyl, or one of Rj, and Rj is hydrogen and each of the others independently is lower alkyl containing up to and including 4 carbon atoms, such as ethyl, 2Q hydroxy-louer alkyl containing up to and including 4 carbon atoms, such as 2-hydroxyethyl or 2-hydroxypropyl, or together are 4- to 7- membered lower alkylene such as 1,4-butylene or 1,5-pentylene, 4to 7-membered, optionally N-louer alkylated sza-louer alkylene, or oxa- or thia-lower alkylene, such as 3-aza-, 3-oxa- or 3-thia-l,525 pencylene, or one of the others is lower alkyl containing up co and including 4 carbon atoms, such as ethyl, and the third is oligohydroxy-louer alkyl such as 2,3,4,5,6-pentahydroxy-l-hexyl uhich is derived from D-gluca=ine, or tuo of Rj, R^ and R. are hydrogen and the other is louer alkyl containing up to and including 4 carbon atcms, such as ethyl, hydroxy-louer alkyl containing up to and including 4 carbon atoms, such as 2-hydroxyethyl, oligo-hydroxy7 lower alkyl containing up to and including 4 carbon atoma, auch as tris(hydroxymethyl)methyl, aaino-lover alkyl containing up to and including 4 carbon atone, such aa 2-aainoethyl,or a group of the formula wherein alk if lower elkylene containing up to and including 4 carbon atoms, such as ethylene, with the proviso that, if R^ is hydrogen and R^ is methyl, Rj is different from 2, 3, 5, 6-pentahydroxy-l-hexyl which is derived from D-glucamine. 4, The invention relates most particularly to pharmaceutical preparations for topical application which contain a compound of the formula 1, uherein R^ and K? have Che meanings just given above and R^, R^ and Rj are hydroxy-louer alkyl containing up to and including 4 carbon acorns, such as 2-hydroxyethyl, or one of Rj, R^ and Rj is hydrogen and che others are lower alkyl containing up co and including 4 carbon atoms, such as ethyl, hydroxy-lower alkyl containing up to and including 4 carbon atoms, such as 2-hydroxyethyl, or 4- to 7— membered oxa-lower alkylene such as 3-oxa-1,5-pentylene.

Host preferably, the invention relates to pharmaceutical preparations for topical application which contain a compound of the formula I, wherein R^ and R^ are as defined above and one of R^, R^ and Rj is hydrogen and the others are lower alkyl containing up to and including 4 carbon atoms, such as ethyl, or 4- to 7-membered 3-oxalower alkylene such as 3-oxa-l,5-pentylene .

The invention relates specifically to the pharmaceutical preparations for topical application referred to in the Examples.

The invention also relates to a process fot the production of pharmaceutical preparations for topical application. The process comprises mixing a compound of the formula I with conventional carriers and/or excipients for topical application.

S0921 Depending on the choice of starting materials and procedures, the compounds of the formula I can be obtained in the form of a possible isomer or of a mixture of isomers, for example optical isomers such as enantiomers or diastereomers, or geometrical isomers such as cis-trans-isomers The optical isomers are in the form of the pure antipodes andZor racemates. Resultant racemates or mixtures of geometrical isomers can be separated into the pure constituents on the basis of the chemico-physical differences between the components. Thus, for example, racemates of optical antipodes can be resolved into the corresponding antimers by methods which are known per se, e.g. by chromatographic methods, by fractional crystallisation, with micro-organisms or enzymes. Further, it is possible to enrich e.g. optical antipodes by conversion of the other antimer in a racemic mixture. Certain conpounds of the formula I are the subject of Tkfcn No. 32.88/85· Hie production of novel conpounds of the formula I ccnprises e.g. reacting an organic carboxylic acid of the formula CH-COOH (Ilia) or a base salt thereof which is different from a salt of the formula I, with an at least equimolar amount of the amine of the formula (mb) ‘5 or an acid addition salt thereof, and, if desired, converting a resultant compound of the formula 1 into another compound of the formula I and/or resolving a resultant mixture of isomers into its individual components.

The molar ratio of acid of the formula (Ilia) and amine of the formula (111b) depends on the choice of desired salt or on the number of substituted amino groups in the corresponding compound of the formula (Illb).

As acid addition salts of amines of the formula (Illb) there are IQ used e.g. corresponding hydrohalides, such as hydrochlorides.

The reaction of a compound of the formula (Ilia) with a compound of the formula (Illb) is preferably conducted in an inert solvent or diluent, if necessary with cooling and heating, e.g. in a temperature range from about 0° to 100’C, preferably at room temperature, in a closed vessel and/or in an inert gas atmosphere, e.g. nitrogen.

Examples of suitable solvents and diluents are: water, alcohols such as lower alkanols, e.g. methanol or ethanol, ethers such as di-lower alkyl ethers, e.g. diethyl ether, cyclic ethers such as dioxane or tetrahydrofuran, ketones such as di-lower alkyl ketones, e.g. acetone, carboxylic acid esters such as lower alkanecarboxylic acid esters, e.g. ethyl acetate, amides such as N,N-di-lower alkylamides, e.g. Ν,Ν-dimethy1 formamide, sulfoxides such as di-lower alkyl sulfoxides, e.g. dimethyl sulfoxide, or mixtures thereof.

The starting materials of the formulae (Ilia) and (Illb) are known.

The starting materials of the formula (Ilia) can be formed e.g. under the reaction conditions from corresponding esters, such as lower alkyl esters, by hydrolysis in the presence of a base, such as an amine, e.g. dimethylamine. An amine of the formula (Illb) can be used e.g. in the form of an acid addition salt, such as a halide, e.g. a hydrochloride, and liberated in the presence of a base, such as an amine.

The pharmaceutical preparations of this invention for topical application contain the compounds of the formula I together with a pharma10 ceutically acceptable carrier or excipient. The daily dosage of the active ingredient depends on the age and individual condition of the patient and also on the mode of application.

Suitable pharmaceutical preparations for topical application are primarily creams, ointments and gels, as well as pastes, foams, tinctures and solutions, which contain from about 0.5 to 5 % of active ingredient.

Creams or lotions are oil-in-water emulsions which contain more than 50 7. oi water. Fatty alcohols are chiefly used as oleaginous base, for example lauryl, cetyl or stearyl alcohol, fatty acids, for example palmitic or stearic acid,liquid to solid waxes, for example isopropyl myristate, wool wax or bees-wax, and/or hydrocarbons, for example petroleum jelly (petrolatum) or paraffin oil. Suitable emulsifiers are surface-active substances with primarily hydrophilic properties, such as corresponding non-ionic emulsifiers, for example Π fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens Tween” is a Trade Mark ); polyoxyethylene fatty alcohol ethers or esters; or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, for exanple sodium lauryl sulfate, sodiun cetyl sulfate or sodiun stearyl sulfate, which are customarily used in the presence oi fatty alcohols, for example cetyl alcohol or stearyl alcohol. Additives to the aqueous phase include agents which reduce water loss through evaporation, for example polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, as well as preservatives, perfumes etc.

Ointments or lotions are water-in-oil emulsions which contain up to 70 Z, preferably however about 20 Z to 50 Z, of water or aqueous phase. The oleaginous phase comprises mainly hydrocarbons, for example petroleum jelly, paraffin oil and/or hard paraffins, which preferably contain hydroxy compounds suitable for improving the water-adsorption, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols, or wool wax. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans Span is a Trade Mark), for exanple sorbitan oleate and/or sorbitan isostearate. Additives to the aqueous phase include humectants, such as polyalcohols, for exanple glycerol, propylene glycol, sorbitol and/or polyethylene glycol, and preservatives, perfumes etc.

Microemulsions are isotropic systems based on the following four components: water, an emulsifier such as a surfactant, e.g. Eumulgin (Trade Mark), a lipid such as a non-polar oil, e.g. paraffin oil, and an alcohol containing a lipophilic group, e.g. 2-octyldodecanol. If desired, ocher ingredients can be added Co the microemulsions.

Greasy ointments are anhydrous and contain as base in particular hydrocarbons, for example paraffin, petroleum jelly and/or liquid 50922 paraffins, and also natural or partially synthetic fat, for example coconut fatty acid triglycerides, or preferably hardened oils, for example hydrated ground nut or castor oil, and also fatty acid partial esters of glycerol, for example glycerol mono- and distearate, and, for example, the fatty alcohols, emulsifiers andZor additives for increasing the water-adsorption mentioned in connection with the ointments.

In the case of gels a distinction is made between aqueous gels, anhydrous gels, and gels having a low water content, and which IQ consists of swellable gel-forming materials. Primarily transparent hydrogels based on inorganic or organic macromolecules are used.

High molecular inorganic components with gel-forming properties are chiefly water-containing silicates such as aluminium silicates, e.g. bentonite, magnesium aluminium silicates, e.g. veegum, or colloidal silica, e.g. aerosil. As high molecular organic substances there are used e.g. natural, semi-synthetic or synthetic macromolecules. Natural and semi-synthetic polymers are derived e.g. from polysaccharides with carbohydrate components of the most widely different kind, such as celluloses, starches, tragacanth, gum arabic, agar-agar, gelatin, alginic acid and salts thereof, e.g. sodium alginate, and their derivatives such as lower alkyl celluloses, e.g. methyl or ethyl cellulose, carboxy- or hydroxy-lower alkyl cellulose, e.g. carboxymethyl cellulose or hydroxyethyl cellulose. The components of synthetic gel-forming macromolecules are e.g. correspondingly sub25 stituted unsaturated aliphatics such as vinyl alcohol, vinyl pyrrolidine, acrylic or methacrylic acid. Examples of such polymers are polyvinyl alcohol derivatives such as polyviol, polyvinyl pyrrolidines such as collidone, polyacrylates and polymethacrylates such as Rohagit s (Trade Mark) or Eudispert (Trade Mark). Conventional additives such as preservatives or perfumes can be added to the gels.

Pastes are creams and ointments containing powdered ingredients which 50821 absorb secretions, such as metal oxides, for example titanium oxide or zinc oxide, and talc andXor aluminium silicates whose purpose it is to bind moisture or secretion present.

Foams are administered from pressurised dispensers and are liquid 5 oil-in-water emulsions in aerosol form, with halogenated hydrocarbons, such as chlorofluoro-lower alkanes, for example dichlorodifluoromethane and dichlorotetrafluoroethane, being used as propellants.

For the oleaginous phase there are used, inter alia, hydrocarbons, for example paraffin oil, fatty alcohols, for example cetyl alcohol, fatty acid esters, for example isopropyl myristate, and/or other waxes. As emulsifiers there are used, inter alia, mixtures of those emulsifiers with primarily hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens Tween is a Trade Mark), and those with primarily lipophilic properties, such as sorbitan fatty acid esters (Spans Span is a Trade Mark). In addition, the conventional additives are used, such as preservatives etc.

Tinctures and solutions generally have an aqueous ethanolic base to which are added, inter alia, polyalcohols, for example glycerol, glycols, and/or polyethylene glycol, as humectants for reducing water loss, and fat-restorative substances, e.g. fatty acid esters with lower polyethylene glycols, i.e. lipophilic substances which are soluble in Che aqueous mixture as substitute for fatty substances which are removed from the skin by the ethanol, and, if necessary, other assistants and additives. 0 9 21 The following Examples illustrate the invention but in no way limit the scope thereof.

Example 1: To a solution of 2 g of 2-(2,6-dichloroanilino)phenylacetic acid in 40 ml of ether are added 2 ml of diethylamine. The solution is refluxed for 10 minutes, then cooled and concentrated under reduced pressure, whereupon diethylasmonium-2-(2,6-dichIoroanilino)phenylacetate crystallises out. The colourless crystals are isolated by filtration (m.p. 110o-115oC with decompos.) and dried at room temperature in a high vacuum.

Example 2: With efficient stirring, a solution of 4.53 g of tris(hydroxyirethyl) ne thyl amine in 10 ml of water is added dropwise at 50821 room temperature and in the course of 10 minutes to a solution of 10 g of 2-(2,6-dichloroanilino)phenylacetic acid in 230 ml of ethyl acetate, whereupon a salt immediately precipitates. The batch is subsequently stirred for half an hour at room temperature and the solvent is removed by rotary evaporation. The white crystalline residue is dissolved in 1 litre of acetone/water (1:1) at about 50°C. The hot solution is concentrated in a rotary evaporator until the first crystals precipitate. The residue is left to crystallise at 0°C, and the precipitated white flocculent crystals are collected on a suction filter and dried in a high vacuum. The resultant tris-(hydroxymethyl)methylaanonium-2~(2,6-dichloroanilino)phenylacetate has a melting point of 202’-204*C.

Example 3: With efficient stirring, a solution of 5.52 g of triethananolamine in 30 ml of ethyl acetate is added dropwise at room temperature and in the course of 10 minutes to a solution of 10 g of 2-(2,6-dichloroanilino)phenylacetic acid in 230 ml or ethyl acetate, whereupon a salt precipitates immediately,The batch is subsequently stirred for about half an hour at room temperature and the solvent is removed in a rotary evaporator. The white crystalline residue is dissolved in a small amount of hot ethanol and crystallised at 0°C.

The white crystals are filtered with suction and dried in a high vacuum. The so obtained triethanolamnonium-2-(2,6-dichloroanilino)phenylacetate melts at 137*-138°C.

Example 4: With efficient stirring, a suspension of 3.89 g of diethanolamine in 30 ml of ethyl acetate is added dropwise at room temperature and in the course of 10 minutes to a solution of 10 g of 2-(2,6-dichloroanilino)phenylacetic acid in 230 ml of ethyl acetate, whereupon a salt precipitates immediately. The batch is subsequently stirred for half an hour at room temperature and the solvent is removed in a rotary evaporator. The yellowish crystalline residue is dissolved in a small amount of boiling ethanol. The solution is left to stand at 0°C and diethanolamnonium-2-(2,-dichloroanilino)-phenylacetate with a melting point of 130°-132°C crystallises out.

Example 5: With efficient stirring, 3.22 g of morpholine in 30 ml of ethyl acetate are added dropwise at room temperature and in the course of 10 minutes to a solution of 10 g of 2-(2,6-dichloroanilino)phenylacetic acid in 230 ml of ethyl acetate. A salt precipitates about 10 minutes after addition of the morpholine. The batch is then stirred for 1 hour at room temperature and the solvent is removed by rotary evaporation. The white crystalline precipitate is dissolved in boiling ethanol. Morpholinium-2-(2,6-dichloroanilino)-phenylacetate with a melting point of 162°-165°C crystallises out at 0°C.

Example 6: With efficient stirring, 4.93 g of diisopropanolamine in 30 ml of ethyl acetate are added dropwise at room temperature and in the course of 5 minutes to a solution of 10 g of 2-(2,615 dichloroanilino)phenylacetic acid in 230 ml of ethyl acetate. A salt precipitates after a short time. The batch is stirred for 1 hour and the solvent is removed by rotary evaporation. The white crystalline precipitate is dissolved in a small amount of hot ethanol and the solution is left to stand at 0°C, whereupon diisopropanolammonium20 2-(2,6-dichloroanilino)phenylacetate with a melting point of 165°170°C crystallises out.

Example 7 : An ointment containing 5 X of diethylasiaoniuin-2-(2,S-dichloroanilino)pheny lacetate ia prepared as follows: Composition propylene glycol high molecular polyalkylene glycol viscous paraffin oil white vaseline microcrystalline wax glycerol para'oenas active ingredient - 44 X 10 Z 12 X 22 X 7 X - 34 X 0.2 X 5 X The active ingredient is dissolved in a mixture of glycerol and propylene glycol and the other components are fused together. The active ingredient solution is then emulsified into the oleaginous phase. If desired, perfume (O.i X) is added after the mixture has been stirred cold.

An ointment containing 0.5 X or 2 X is prepared in similar manner.

Exaaple 8: A transparent hydrogel containing 5 X of diethylammonium2-(2,6-dichloroanilino)phenylacetate is prepared as follows: Composition active ingredient 5 7. propylene glycol 10 - 20 Z isopropanol 20 Z hydroxypropylmethyl cellulose 2 % water to make up 100 7.

The hydroxypropylmethyl cellulose is swelled in water and the active ingredient is dissolved in a mixture of isopropanol and propylene glycol. The active ingredient solution is then mixed with the 1θ cellulose derivative and, if desired, perfume (0.1 7.) is added.

A gel containing 0.5 Z or 2 Z of active ingredient is prepared in similar manner.

Example 9 : A transparent hydrogel containing 5 Z of diethylaamonium 2-(2,6-dichloroanilino)phenylacetate is prepared as follows: Composition active ingredient 5 7. propylene glycol 20 Z isopropanol 20 Z acrylic acid polymer 2 7. triethanolamine 3 Z water to make up 100 Z The acrylic acid polymer and water are dispersed and neutralised with triethanolamine. The active ingredient is dissolved in a mixture of isopropanol and propylene glycol. The active ingredient solution is then mixed with the gel. If desired, perfume (0.1 Z) can be added.

A gel containing 0.5 Z or 2 Z of active ingredient can be prepared in similar manner.

Example 10 : A transparent microemulsion containing 5 Z of diethylammonium 2-(2,6-dichloroanilino)phenylacetate is prepared as follows: Composition active ingredient 5 Z cetyl stearyl alcohol 27 Z polyol fatty acid ester 15 Z glycerol 4 Z water to make up 100 Z The cetyl stearyl alcohol and polyol fatty acid ester are heated to 10 95°C and the active ingredient is dissolved therein. A mixture of water and glycerol, which has been heated to 95’C, is added. If desired, 0.2 Z of preservative is added. The resultant microemulsion is cooled, with stirring, and perfume (0.1 Z) is added, if desired. Transparent emulsions containing 0.5 Z or 2 Z of active ingredient are prepared in similar manner.

Example 11: A lotion containing 5 Z of diethylammonium-2-(2,6-dichloroanilinolphenylacetate ie prepared as follows: Composition active ingredient 5 Z mono- and diglycerides of higher saturated fatty acids with potassium stearate 8 Z polyoxyethylene cetyl stearyl ether 2 Z decyl oleate 5 Z propylene glycol 20 Z parabenes 0.2 Z demineralised water to make up 100 Z The active ingredient and the parabenes are dissolved in water and propylene glycol. Then polyoxyethylene cetyl stearyl ether is added 50821 to the above solution. Decyl oleate and the glycerides of fatty acids with potassium stearate are fused together and emulsified into the aqueous phase. The lotion is stirred cold and,if desired, perfume (0.1 Z) is added.

Example 12.· A solution containing 5 2 of diethylammonium-2-(2,6-dichloroanilinolphenylacetate is prepared as follows: Composition active ingredient 5 Z polyoxyethylene sorbitan fatty acid ester 10 X ethanol 20 Z triglyceride (liquid) 65 Z The active ingredient is dissolved in ethanol and the polyoxyethylene sorbitan fatty acid ester is dissolved in liquid triglyceride. The two solutions are combined and, if desired, perfume (0.1 Z) is added.

Solutions containing 0.5 Z and 2 Z respectively of active ingredient are prepared in similar manner.

Example 13: An ointment containing 5 Z of diethylannnonium-2-(2,6dichloroanilino)phenylacetate is prepared as follows: Composition active ingredient 5 Z mono- and diglycerides of higher saturated fatty acids with potassium stearate 17 Z decyl oleate 5 Z propylene glycol 20 Z demineralised water to make up 100 Z The active ingredient is dissolved in propylene glycol and water. Mono- and diglycerides of saturated fatty acids with potassium stearate are fused together with decyl oleate. The aqueous phase is then added to the oleaginous phase and emulsified. If desired, perfume (0.1 Z) is added.

A cream containing 0.5 Z and 2 Z respectively of active ingredient is prepared in similar manner.

Example 14; An ointment containing 5 Z of diethylaanonium 2-(2,6dichloroanilino)phenylacetate is prepared as follows: IQ Composition active ingredient 5 Z propylene glycol 12 Z vaseline, white 28 Z wax (microcrystalline) 2 Z sorbitan fatty acid ester 25 Z demineralised water to make up 100 Z The active ingredient is dissolved in propylene glycol and water.

The vaseline, wax and sorbitan fatty acid esters are fused together. The active ingredient solution is then emulsified into the oleaginous phase and, if desired, perfume (0.1 Z) is added.

An ointment containing 0.5 Z and 2 Z respectively of active ingredient is prepared in similar manner.

Example 15 : A lotion containing 2 Z of diethylaanonium 2-(2,6dichloroanilino)phenylacetate is prepared as follows: Composition active ingredient 2 Z high molecular polyalkylene glycol 14 Z liquid triglyceride 5 Z viscous paraffin oil 13 Z glycerol sorbitan fatty acid ester 10 Z demineralised vater to make up 100 Z The active ingredient is dissolved in polyalkylene glycol and water. Triglyceride, paraffin oil and glycerol sorbitan fatty acid ester are fused together. The aqueous phase is then emulsified into the oleaginous phase and, if desired, perfume (0.1 Z) is added. A lotion containing 0.5 Z of active ingredient is prepared in similar manner.

Ointments, creams, gels, microemulsions, lotions and solutions containing 0.5 Z, 2 Z or 5 Z of the compounds of Examples 1 to 6 are prepared in the same way as in Examples 7 to 15.

Claims

1. A pharmaceutical preparation for topical application which contain* a compound of the formula N—8. ‘4 (I) R, wherein R^ is e group of the formula ‘5 X? and Xj are hydrogen and X^ it 2,6-dichloroanilino, and is hydrogen, and each of Rj, R^ and Rj independently ia hydrogen t an aliphatic radical, or two of Rj, R^ and Rj together are a bivalent aliphatic radical, unsubstituted or substituted or interrupted by aza, oxa or thia, with the proviso that at least one of Rj, R^ and Rj is different from hydrogen and the additional proviso that, if Rj is hydrogen and R^ is methyl, Rj is different from 2,3,4,5,6-pentahydroxy-l-hexyl which is derived from D-glucamine, optionally in tbe form of an isomer, together with conventional carriers and/or excipients for topical application.

2. A pharmaceutical preparation for topical application according to claim 1, which contains a compound of the formula I, wherein R^ and R? are as defined in claim 1 and each of Rj.R^ end Rj independently is hydrogen, a lower alkyl radical which is unsubstituted or substituted by amino, a group of the formula or hydroxyl, or two of Rj, R^ and R. are 4- to '-membered lower alkylene or 4- to, 7-membered lower alkylene which is interrupted by optionally lower alkyl-substituted aza, or by oxa or chia, with the proviso that at least one of Rj, R^ and Rj is different from hydrogen, together with conventional carriers and excipients for topical application.

3. A pharmaceutical preparation for topical application according to claim 1, which contain» a compound of the formula I, wherein R^ and Rj are as defined in claim 1 and each of R^, R^ and R^ independently is louer alkyl containing up to and including 4 carbon atoms, or hydroxyl-lower alkyl containing up to and including 4 carbon atoms, or one of R^, R^ and R^ is hydrogen and each of the others independently is lower alkyl containing up to and including 4 carbon atoms, hydroxy-lower alkyl containing up to and including 4 carbon atoms, or together are 4- to 7-membered lower alkylene, 4. - to 7-membered, optionally H-lower alkylated aza- lower alkylene, or oxa- or thia-lower alkylene, or one of the others is lower alkyl rnnrain-ing up. to and including 4 carbon atoms, and the third is oligo-hydroxy-lower alkyl, or two of R^, R^ and R^ are hydrogen and the other is lower alkyl containing up to and including 4 carbon atoms, hydroxy-lower alkyl containing up to and including 4 carbon atoms, oligo-hydroxy- lower alkyl containing up to and including 4 carbon arenas, amino-lover alkyl containing up to and including 4 carbon atoms, or a group of the formula wherein alk is lower alkylene containing up to and including 4 carbon atoms, together with conventional carriers and excipients for topical application.

4. A pharmaceutical preparation for topical application according co claim 1, which contains a compound of the formula I, wherein R^ and R^ are as defined in claim 1 and R^, R^ and R^ are hydroxy-lower alkyl containing up to and including 4 carbon atoms, or one of R^, R^ and R$ is hydrogen and the others are lower alkyl containing up to and including 4 carbon atoms, hydroxy-lover alkyl containing up to and including 4 carbon atoms, or 4- eo 7-membered oxa lower alkylene, together with conventional carriers and excipients for topical application. 50821

5. A pharmaceutical preparation for topical application according to claim 1, which contain· a compound of tbe formula I, wherein and B? * Te >s defined In claim 1 and aae of R^, R^ and R^ it hydrogen and the other* are lower alkyl containing up to and including 4 carbon atom*, or together 3-«xa-l,5-pentylene, together with conventional carriers and excipient* for topical application.

6. A pharmaceutical preparation according to claim 1 which contains diethylais*onium-2-(2,6-dichloroanilino)phenylaeetate, together with conventional carrier* and excipient* for topical application.

7. · A pharmaceutical preparation for topical application according to claim 1 which contain* tris-(hydroxymethyl)methylannonium-2-(2,6dichloroanilino)phenylacetate, together with conventional carriers and excipients for topical application.

8. A pharmaceutical preparation for topical application according to claim 1 which contain* triethanolais&oniuis-2-(2,6-dichloroanilino)pbenylacerate, together with conventional carriers and excipient* for topical application.

9. A pharmaceutical preparation for topical application according to claim 1 which contain* diethaaol*B«aonium-2-(2,6-dichloroanilino)phenylacetate, together with conventional carriers and excipients for topical application.

10. A pharmaceutical preparation for topical application according to claim 1 which contain* morpholiniunr2-(2,6~dichloroanilino)phenylacetate, together with conventional carriers and excipients for topical application.

11. , A pharmaceutical preparation for topical application according to claim 1 which contains diisopropanolammonium-2-(2,6-dichloroanilino)phenylacetate, together with conventional carriers and excipients for topical application.

12. A pharmaceutical preparation for topical application according to claim 1 substantially as described with reference to any of Examples 7 to 15.

13. , A process for che production of a pharmaceutical preparation for topical application, which process conprises mixing a compound of the formula V/ 5 *2 Ir, ι * R. (I) wherein is a group of the formula *ΐχ Λ ./ \ in wherein X, and X, are hydrogen and X, is (Ila) . 2,6-dichloroaniline, and Rj is hydrogen, and each of Rj, R^ and R. independently is hydrogen, an aliphatic radical, or two of R^, R^ and Rj together are a bivalent aliphatic radical, unsubstituted or substituted or interrupted by aza, oxa or thia, with the proviso that at least one 15 of Rj, R^ and Rj is different from hydrogen, and the additional proviso that, if Rj is hydrogen and R^ is methyl, Rj is different from 2,3,4,5,6-pentahydroxy-l-hexyl which is derived from D-glucamine, optionally in the form of an isomer, together with conventional carriers and/or excipients for topical application.

14.. A process according to claim 13 substantially as described with reference to any of Examples 7 to 15,

15. A pharmaceutical preparation when produced by a process claimed in claim 13 or 14.

16. λ pharmaceutical preparation according to any one of claims 1 to 12, which contains about 0.5 to 5Z by weight of active ingredient, together with conventional pharmaceutical carrier! and/or excipients.