LT3804B - Process for preparing pharmaceutical preparation for treating psoriatic diseases - Google Patents

Abstract

The use of alkyl phosphoric acid compounds of the formula I R - Y - PO@ - X - R1 1 where, in formula I, R is a saturated or unsaturated hydrocarbon radical with 12 to 24 C atoms or where R is the group -CH2-CHR3-CH2-Z-R4 and R3 is a C1-C6-alkoxy group or a C1-C6-alkoxymethyl group, Z is oxygen or sulphur and R4 is a C1-C24-alkyl radical, X is an oxygen atom, NH or NR2 and Y is an oxygen atom or NH, R1 is a C1-C8-alkyl group, or in which R1 is a C2-C8-alkyl group which is unsaturated and/or substituted by halogen, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, tri-C1-C6-alkylamino, hydroxyl, carboxyl, C3-C8-cycloalkyl or phenyl, for the preparation of a pharmaceutical composition for the treatment of psoriasis.

Description

The present invention relates to the use of alkyl phosphoric acid and its salts in the preparation of pharmaceutical preparations for the treatment of psoriasis and related disorders, and to a process for the preparation thereof.

In the present invention, psoriasis-type disorders are skin disorders that develop with hyperkeratosis, in particular psoriasis, arthropathia psoriatica, parapsoriasis. Currently, corticosteroids are the most commonly used treatment for psoriasis. In severe cases even cytostatics (eg methotrexate) are used. All these substances cause severe and serious side effects.

Alkylphosphoric acid compounds of Formula I are known antitumor agents.

Such compounds, or their physiologically acceptable salts, have been found to treat psoriasis and related conditions. Therapeutic doses of these compounds cause no or very minor side effects. The activity of the compounds of the formula I for topical therapy far exceeds that of the dermatics (keratolytics and corticoids) commonly used in psoriasis.

The pharmaceutical compositions of the present invention are characterized in that the active ingredient is at least one compound of the general formula I:

R - Y - ΡΟ ₂ θ - X - Ri (I) wherein: R is a saturated or unsaturated hydrocarbon radical having from 12 to 24 carbon atoms which may be substituted by halogen, or R is -CH2-CHR3-CH2-. z-R 4 group wherein R 3 is Ci-C ₆ alkoxy or C 4 -C 6 alkoxymethyl group, z is oxygen or sulfur and R4 is C1-C24 alkyl;

X is an oxygen atom or a group NH or NR ₂ wherein R ₂ is a saturated C 1 -C 6 or unsaturated C 3 -C 6 alkyl radical; saturated C 1 -C 6 alkyl;

Y is an oxygen atom or an NH group; and

R 1 is C ₁ -C ₈ alkyl or unsubstituted C ₂ -C ₈ alkyl substituted with one substituent such as halogen, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 8 trialkylamino, hydroxy, carboxyl, C 5 -C 8 -cycloalkyl, or phenyl;

and wherein R 1 may be, inter alia, 2-tetrabutyloxycarbonylaminoethyl, 2-tetrabutyloxycarbonylethyl, 2,3-isopropyldienedioxypropyl- (1), 2,3-dibenzyloxypropyl- (1), 1,3-dibenzyloxypropyl- (2) or 2,3- dihydroxypropyl- (1); and when X is a NH group, Ri is 2,3-dihidroksipropilo- (l) a group of Ci-C ₈ -alkyl or unsaturated C ₂ -C ₈ alkyl substituted with a substituent such as halogen, amino C₁-C₆-alkylamino, C A -C ₆ -dialkylamino group, a C 1-8 trialkylamino group, a hydroxyl, a carboxyl, a C 3 -C ₈ -cycloalkyl or phenyl, or a pharmaceutically acceptable salt thereof.

The most active substances are: hexadecylphosphocholine, oleylphosphocholine, N, N- (2-chloroethyl) amide of hexadecylphosphoric acid. Formula I includes enantiomers and diastereomers. If the compounds are racemates, they can be resolved into optically active isomers by any known means, for example, with optically active acids. When enantiomers or diastereomers are used as starting products, the resulting final product is the corresponding pure optically active or diastereomeric compound.

According to the present invention, preferably R is alkyl of a given chain length bonded to the oxygen of the glycol moiety via a terminal carbon atom or via a carbon atom in the middle of the alkyl chain (e.g. via a 2 or 3 carbon atom or any other middle carbon atom). . This alkyl chain may be straight or branched. The alkyl chain of the R radical may have 1, 2 or 3 double bonds which may be mixed and / or may contain halogen substituents. The halogen atoms may be fluorine, chlorine or bromine. The R radical may contain from 1 to 3 such halogen atoms; they may be attached to one or more carbon atoms of the R radical. Preference is given to radicals having one or two double bonds in addition to straight-chain saturated alkyls. Particularly suitable are R substituents having 14-20 carbon atoms, preferably 15-20, preferably 16-20 carbon atoms. Examples of halogen R radicals include: chlorhexadecyl, bromhexadecyl, fluorhexadecyl, 9,10-dibromoctadecyl, 2,3-dibromoctadecyl, 15,16-dibromohexadecyl, bromotetradecyl. Examples of unsaturated radicals R include: 9-octadecenyl (an oleyl alcohol residue, in formula I R is this 9-octadecenyl radical), 15-hexadecenyl, 9,12-octadecadienyl (linoleyl). If there is more than one double or triple bond, they are conjugated. Examples of saturated and unsubstituted R include: tetradecyl, hexadecyl, octadecyl. A major group R is -CH ₂ -CHR ₃ -CH ₂ -Z ₃

R 4 when Y and X are oxygen and R 1 is a C 1 -C 6-trialkylamino group (especially trimethylamino) linked to the X chain from C 2 -C 3 atoms; here the positive charge on the trialkylamine cation counteracts the phosphoric acid anion.

When R3 and R4 are alkoxy groups, the term "methoxy" is usually used. The C 1 -C 24 alkyl radical of the R 4 group generally has from 10 to 20, in particular from 12 to 28, carbon atoms and is predominantly unbranched.

When R 1 or R 2 (in the case X is -NR 2 -) is an unsubstituted alkyl group, it has 1-6, preferably 1-4 carbon atoms. When R 1 or R 2 is unsaturated alkyl, it is composed of

3-6 carbon atoms, and there must be at least one single C-C bond between the unsaturated group and X. Most commonly are Cs-Ce-alkenyl groups. Examples include aula, butenyl, pentenyl, hexenyl.

When R 1 or R 2 is substituted, then it is a straight chain alkyl or alkenyl; in this case Ri consists of 2 to 6 carbon atoms, which are usually substituted with alkyls or alkenyls substituted in the ω-position, for example ethyl or unbranched propyl in the 2-position in the ethyl and in the 3-position in the propyl ).

When R 1 is 2-tetrabutyloxycarbonylethyl or 2-tetrabutyloxycarbonylaminoethyl, then the most common form is D or L. As a substituent on Ri, trialkylamoniomethyl (especially when X is an oxygen atom) is most important, and trialkyl radicals in this group are usually composed of 1-3 carbon atoms. Trimethylammonioethyl is particularly important. In this case, the compounds of formula I refer to phosphatidylcholine derivatives. When the substituent is C 5 -C 8 -cycloalkyl, it is preferably substituted with 3 to 6 carbon atoms (e.g., cyclopropyl to cyclohexyl). In the case of substituted dihydroxypropyl, the structures most commonly referred to are sn-1,2-dihydroxypropylamino- (3) or sn-2,3-dihydroxypropylamino- (l).

Examples of the most important compounds of formula I are: oleyl phospho- (N, N, N-trimethyl) propanolamine, oleyl phospho- (N, N, N-trimethyl) butanolamine, oleyl phospho- (N, N, N-trimethyl) ) pentanolamine, oleyl-phosphopropanolamine, oleyl-phosphobutanolamine, oleyl-phosphoserine, oleyl-phospho-ethanolamine, oleyl-phosphoglycerin, hexadecyldecyl-phospho- (N, N, N-trimethyl) -propanolamine, 1-octadecyl-2-methyl-sn-glycine ( for example, ET-18-OCH3, see VFR patent 2619686), l-hexadecylmercapto-2-methoxymethylpropanol-3-phosphocholine (ilmofzine).

Salts are understood to be internal salts (for example, when R is trimethylammonium alkyl) or salts with pharmacologically acceptable cations.

The medicaments of the present invention, i.e. compounds of formula I, may be internal salts, for example when R has an ammonium group. When the inner salts do not form, or if the R radical has no basic groups, then the negative charge of the phosphoric acid residue is neutralized with a physiologically acceptable cation. Such physiologically acceptable cations may include: alkali metal cations (Na, K), earth alkaline metal cations (Mg, Ca) or organic amine cations such as guanidine, morphol, cyclohexylammonium, ethylenediammonium, piperizonium (in the last two cases monobasic or dibasic). ) or an amine of formula NR _a RBR _c wherein R _a -R _c are identical or different and are hydrogen, Ci-C2 alkyl or hydroxyethyl groups forming cation.

In the case of ammonium cations of the formula NR _a R _b R _c , mention should be made first of all of the ammonium cation or of the ammonium cation which is substituted with 1-3 C 1 -C 2 alkyl groups or 1-2 hydroxyethyl groups. In this way, the negative charge of the compounds of formula I is neutralized by a basic low molecular weight mono-, di- or trialkylamine group or by an additional physiologically acceptable cation.

The preparation of the active ingredient of formula (I) is substantially clear and can be accomplished by known methods. The backbone can be obtained by the reaction of a compound of formula ROH or a functional derivative thereof with a compound of formula HXRi under the action of phosphorus oxychloride and triethylamine and acid cleavage; where R, R _t and X have the meanings given above.

The pharmaceutical compositions of the present invention contain, as an active ingredient, at least one compound (component) of formula I, optionally together with other pharmacologically or pharmaceutically active substances.

One dose of medication for the treatment of psoriasis and related conditions

1-1000 mg, preferably 5-500 mg, preferably 10-100 mg of Component I (Component 1 = sum of the individual masses of the compounds of Formula I) administered orally, parenterally, rectally, vaginally or by inhalation.

In the case of a preparation of 2 or more compounds of the formula I, these amounts are included in the total amount of component 1. Analogously, the amount of component 1 is calculated, including the dosage and weight of the respective medicaments as defined in the invention. Component 1 is understood to mean the individual compounds of formula I or their physiologically acceptable salts. For example, for topical application to the skin or mucosa, the weight of component 1 is 0.1 to 100 mg, preferably 0.1 to 500 mg.

The preparation may be administered in the form of tablets, capsules, pills, peas, suppositories, ointments, gels, creams, powders, powders, aerosols or liquids. Liquid form solutions in oil, alcohol or water, suspensions and emulsions. The most important form is tablets containing 10-100 mg of component 1 or solutions containing 0.01-10% by weight of component 1. A single dose of Component I (total amount of compounds of Formula I) may for example be:

a) orally, from 1 to 1000 mg, preferably from 10 to 500 mg;

b) for parenteral administration (e.g., intravenous, intramuscular), 1-1000 mg, preferably 10-500 mg;

c) for inhalation administration (solutions or aerosols), 1-1000 mg, preferably 10-500 mg;

d) for rectal or vaginal administration, 1 to 1000 mg, preferably 10 to 500 mg;

e) topical treatment of the skin or mucous membranes (e.g., solutions, lotions, emulsions, ointments, etc.), 0.1-1000 mg, preferably 0.1-500 mg, in the presence of component 1 (general formula I) compound content) 0.01-12% by weight, preferably 0.1-8% by weight.

It is recommended to take 1-3 tablets 3 times a day containing 1-100 mg of component 1 or to inject intravenously one ampoule of 1-10 ml containing 1-100 mg component 1 1-3 times a day. The minimum daily oral dose is 1 mg and the maximum dose should not exceed 1000 mg.

For the treatment of cats and dogs, a single dose of component 1 is 0.01-60 mg / kg body weight, and a parenteral dose is 0.01-60 mg / kg body weight.

For the treatment of horses and rhinitis, the single oral dose of component 1 is 0.05-100 mg / kg body weight and the parenteral dose is 0.05-100 mg / kg body weight.

The acute toxicity of compounds of formula I in mice (expressed as MD mg / kg, according to Miller and Tainter, Proc. Soc. Exper. Biol. A. Med., 57, 261 (1944)) is 300-1000 mg / kg. .

These drugs may be prepared by known methods. Known pharmaceutical excipients, conventional carriers and diluents may also be used.

Carriers and diluents include the following, which are recommended as excipients in the pharmaceutical, cosmetic, and related fields: Ulman, Enzyklopadie der Technische Chemie, Bd.4, S.1-39; Journal of Pharmaceutical Science, 52, 918 (1963); H.F. Zetch-Lindenwald, Hilfsstoffe in Pharmazie und grenzende Gebiete; Pharm. Ind., 2 Teil, 1961, S.72; Dr. H.F. Fiedler; Verzeichnis der Hilfsstoffe fur Pharmazie, Cosmetics & Gentlemen Gebiete, Cantor KG. Aufendorf in Wurttemberg, 1981.

Examples include: gelatine, natural sugar, crude sugar and milk sugar, lecithin, pectin, starch (for example, corn starch), cyclodextrins and their substitutes: polyvinylpyrrolidone, polyvinyl acetate, acacia, alginic acid, tylose, (e.g., colloidal), cellulose and its substitutes (e.g., cellulose ether wherein the hydroxy groups of the cellulose are partially substituted by lower saturated alcohols and / or lower aliphatic oxyalcohols such as methyloxypropylcellulose, methylcellulose, hydroxypropylmethyl); fatty acids as well as fatty acids with 1 to 12 carbon atoms, especially saturated (e.g. stearic) magnesium, calcium or aluminum salts, emulsifiers, fats and oils, especially vegetable (for example, arachis oil, castor oil, olive oil, sesame oil) , cotton oil, corn oil, wheat oil, sunflower oil), fish oil, including hydrogenated; mono-, di- and triglycerides of C12H24O2 to C18H36O2 saturated fatty acids and their mixtures, pharmaceutically acceptable lower or higher alcohols and polyglycols as polyethylene glycol, and their substitutes, and aliphatic saturated or unsaturated fatty acids (especially 2 to 22 carbon atoms, 10 to 18 carbon atoms) esters with monohydric (1 to 20 carbon atoms) or polyhydric alcohols such as glycols, glycerol, diethylene glycol, pentaerythritol, sorbitol, mannitol, etc., which may also be esterified; citric acid esters with primary alcohols, acetic acid, benzyl benzoate, dioxolane, tetrahydrofurfuryl alcohol, triglycol ether with C 1 -C ₁₂ alcohols, diethylacetamides, lactamides, lactates, ethyl carbonates, silicones (especially polydimethylsiloxane), calcium, sodium phosphate, magnesium carbonate and the like.

In addition, disintegrants such as cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose or microcrystalline cellulose may be mentioned as excipients. Known materials for sheathing may also be used. Such materials are: polymers and copolymers of acrylic acid and / or methacrylic acid and / or its esters; copolymers of acrylic and methacrylic acid esters with low residual ammonium groups (e.g. Eudragit® RS), acrylic and methacrylic acid copolymers and trimethylammoniomethacrylate (e.g. Euragit® RS); polyvinyl acetate; fats, oils, waxes, fatty alcohols, hydroxypropylmethylcellulose phthalate or acetate succinate; cellulose, starch acetate phthalates or polyvinyl acetate phthalates; carboxymethylcellulose, methylcellulose phthalate, succinate, phthalate succinate, as well as a semicester of methylcellulose and phthalic acid; ethylcellulose and its succinate; shellac; gluten, zein, ethylcarboxyethyl cellulose; a copolymer of ethacrylate and maleic anhydride; a copolymer of vinyl methyl ether and maleic anhydride; copolymers of styrene and maleic acid; Copolymer of 2-ethylhexyl acrylic acid and maleic anhydride; copolymer of vinyl acetate and crotonic acid; glutamic acid / ester copolymer; glyceryl monooctanoate of carboxymethylcellulose; cellulose acetic succinate, polyarginine.

As plasticizers for the shell may be: citric and tartaric acid esters (acetyl triethyl, acetyl tributyl, tributyl, triethyl citrate); glycerol and glycerol esters (glycerol diacetate, triacetate, acetylated monoglyceride, castor oil); phthalic acid ester (dibutyl, diamyl, dimethyl dipropyl phthalate), di- (2-methoxy) - or ethoxyethyl phthalate, ethyl phthalyl, butyl phthalethyl and butyl glycolate; alcohols (propylene glycol, polyethylene glycol of various lengths), adipates (diethyl adipate, di- (2-methoxy) - or ethoxyethyl adipate); benzophenone; diethylene glycol dipropionate; ethylene glycol diacetate, di8 propionate; tributyl phosphate, tributyrin; polyethylene glycol sorbitan monooleate (polysorbates as polysorbate 80); sorbitan monooleate.

The solutions and suspensions may be formulated with water or physiologically compatible organic solvents such as ethanol, propanol, isopropanol, 1,2-propylene glycol, glycerol-C 1 -C ₁₂ alkyl ether, in particular 1-glycerol-C 1 -C ₁₂ alkyl ether, e.g. , glycerol-1-n-propyl ether, glycerol-1-n-hexyl ether, glycerol-1-n-nonyl ether, polyglycols and their derivatives, dimethylsulfoxide, fatty alcohols, triglycerides, partially etherified glycerol, paraffins and the like.

Non-toxic parenterally acceptable diluents and solvents, such as water, 1,3-butanol, ethanol, can be used as solutions and suspensions for injection.

1,2-propylene glycol, polyglycols mixed with water, Ringer's solution, saline and table fats, including synthetic mono- or diglycerides, or fatty acids such as oleic acid.

Known and conventional solvents and emulsifiers may be used to prepare the formulations. Polyvinylpyrrolidone, fatty acid and sorbitan esters such as sorbitantrioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate and other ethoxylated fatty acid and sorbitan esters, fatty acid esters of polyoxyethylene, polyoxyethyl fatty acids, , condensation products of alkyl phenols or fatty acids, as well as l-methyl-3- (2-hydroxyethyl) imidazolidone- (2). "Polyoxyethylated" as used herein means that the substances contain polyoxyethylene chains having a degree of pilomerization of between 2 and 40, in particular between 10 and 20. Such polyoxyethylated materials may be obtained from compounds with hydroxyl groups (e.g., mono- or diglycerides, or unsaturated compounds, e.g. such as those containing a butyric acid radical) in an exchange reaction with ethylene oxide, for example 40 moles of ethylene oxide per mole of glyceride.

Examples of oleoglycerides include olive oil, arachis oil, castor oil, cotton oil, corn oil. See also Dr. H.F. Fiedler, Verzeichnis der Hilfsstoffe fur Pharmazie, Kosmetik und Grenzende Gebiete, 1971, S. 191-195.

Additionally, preservatives, stabilizers, buffers such as calcium hydrogen phosphate, sweeteners, dyes, antioxidants and complex binders (e.g. ethylenediaminetetraacetic acid) can be added. If necessary, physiologically acceptable acids or buffers having a pH range of 3 to 7 are added to stabilize the molecules of the active ingredient. In particular, the pH is preferably between neutral and weak acid (up to pH = 5).

The pharmaceuticals may be formulated with the substances listed above and cream or liquid hydrocarbons such as petroleum jelly or paraffin or paraffinic hydrocarbons and polyethylene gels, fats and vegetable or animal oils which may be partially hydrogenated or synthetic fats such as C ₈ -C ₈ glycerides of fatty acids, and beeswax, cetyl palmitate, wool wax, wool alcohol; fatty alcohols such as cetyl alcohol, stearyl alcohol; polyethylene glycols having a molecular weight of 200 to 20,000; liquid waxes such as isopropyl myristate, isopropyl stearate, ethyl oleate; emulsifiers such as sodium, potassium, ammonium salts of stearic or palmitic acid as well as triethanolamine stearate, alkali metal salts of butyric acid, ricinic acid, salts of sulphonated fatty alcohols such as sodium lauryl sulphate, sodium cetyl sulphate, sodium stearyl sulphate, bile acid, such as cholesterol, partial esters of polyhydric alcohols and fatty acids such as ethylene glycol monostearate, glyceromonostearate, pentaerythritmonostearate, partial sorbitol ester of fatty acids, sorbitol polyoxyethylene ether, polyoxyethylene fatty acid ester and fatty acid ester of fatty acids.

Sodium metabisulphite, ascorbic acid, alkyl esters of gallic acid, butylhydroxyanisole, nordihydroguaiartic acid, tocopherol as well as tocopherol + synergists (substances that bind to heavy heavy metals such as lecithin, ascorbic acid) may be used as antioxidants. The addition of synergists significantly increases the antioxidant action of tocopherols.

Examples of preservatives include sorbic acid, p-hydroxybenzoic acid ester (e.g. lower alkyl ester), benzoic acid, sodium benzoate, trichloroisobutyl alcohol, phenol, cresol, benzethonium chloride and formalin derivatives.

Methods of using the compounds of formula (I) in the manufacture of a medicament are conventional standard methods. The active ingredient and the excipients or carriers are pulverized, homogenized and mixed well (for example, by a simple mixer) at 20-80 ° C, preferably 20-50 ° C, preferably at room temperature.

Reference is generally made to the following sources: Sucher, Fuchs, Speiser, Pharmazeutische Technologie, Time Verlag, Studgardt, 1978.

The drugs can be applied to the skin, mucous membranes or as internal drugs, for example, by oral, parenteral, pulmonary, rectal, nasal, vaginal, lingual, intracardiac, intravenous, arterial, intramuscular, intraperitoneal, subcutaneous. Parenteral preparations should be sterile or sterilized products.

The concentration (total amount, component 1) of the compounds of formula (I) in the form of a topical formulation is 0.01-12% by weight, preferably 0.05-10% by weight, preferably 0.1-8 or 0.5-6% by weight.

For the treatment of psoriasis, the compounds of Formula I (Component 1) are commonly administered topically, for example, as solutions, infusions, suspensions, emulsions, powders, gels, creams, pastes, lotions or shampoos. The most commonly used non-aqueous preparations are concomitant administration of salicylic acid and / or urea. Detergents for the manufacture of which surfactants are added are described in VFR application 36 03 859. Urea may be present in the urea-tenside compound or in free form. Naturally, preparations containing neither urea nor salicylic acid can be used. The concentrations (total amount) of the compounds of the formula I used are from 0.1 to 10% (w / w), preferably from 0.5 to 8%, preferably from 1 to 6%; the concentration used for salicylic acid is 0.1-10%, preferably 0.2-8%, preferably 5-15%.

For external treatment, it is preferable to use the compounds of Formula I (Component 1) with at least one alkylglycerol having from 2 to 12 carbon atoms in the alkyl group bonded etherically to the primary or secondary OH glycerol group. Such alkylglycerols improve the performance of the compounds. In this case, it is preferable to use alkylglycerols having from 3 to 9 carbon atoms, singly or in combination.

Particularly effective are medicines containing:

(a) one or more compounds of formula I (component 1); and

(b) alkylglycerol of formula (Π):

H ₂ C - Q - Rs i

HC -O - R <,

I

H ₂ C - OH (H) wherein one of the radicals R ₅ and R 6 is an alkyl group having 2 to 12 carbon atoms and the other radical is a hydrogen atom, as well as common pharmaceutical additives and diluents.

The preparation of alkylglycerols is known, for example, from DE-OS 33 43 530.8

Preferably a mixture of water and alkylglycerols (nonyl or octylglycerol, hexyl or pentylglycerol and propyl or ethylglycerol) and water is preferred. Such a topical formulation contains from 1 to 100 mg of a compound of formula I (component 1, i.e., the total amount of compounds of formula I) per milliliter of alkyl glycerol of formula (II) or corresponding alkyl glycerol and water. Such a mixture will hereinafter be referred to as a cascade.

The amount of component 1 in mg / ml of the cascade is represented by a specific index: a cascade mixture containing, for example, 10 mg / ml of component 1, is referred to as cascade 10 and the mixture containing 60 mg / ml of component 1 is referred to as cascade 60. .

Preferred alkylglycerol-water mixtures include nonylglycerol, octylglycerol, hexylglycerol, pentylglycerol, propylglycerol and ethylglycerol. Such aqueous mixtures contain generally 3 of the aforementioned glycerol ethers, one of which is lower (ethyl, propyl), one is middle (pentyl, hexyl) and one is higher (octyl, nonyl); in addition, the mass of the lower ether is approximately equal to the sum of the masses of the other two glycerol ethers. The weight of the water is approximately equal to the weight of the lower glycerol ether and is, for example, half of the total weight of said glycerol ethers. An example of such a glycerol ether-water mixture is:

Water Glycerine propyl ether Glycerine hexyl ether Glycerin nonyl ether Parts of mass: 2 2 1 1 Water Glycerin Glycerin Glycerin ethyl ether pentyl ether octyl ether Parts of mass: 2 2 1 I

For topical use, the drug is the alkyl glycerol of formula (II). For example, in order to cure psoriasis and related conditions, it is recommended to rub the required area of skin 2-3 times a day in a cascade of 10 to 80. No undesirable side effects have been observed so far.

The preparation of the compounds of formula (I) in the form of a (component 1) cascade (e.g., cascade 1 to 100, preferably cascade 40 to 60) is suitable for the manufacture of suppositories by rectal treatment. They can also successfully treat psoriasis and related conditions.

A particularly suitable carrier component of Component 1 is a mixture of 4 parts by weight of water, 4 parts by weight of propylglycerol and 2 parts by weight of hexylglycerol and nonylglycerol.

For preparations containing a mixture of component 1 and glycerol ether or glycerol ethers of formula (Π), 10000 to 7, preferably 100 to 10, preferably 100 to 10, preferably 100 to 10, preferably 100 to 10, preferably 100 to 10, 3016 parts by weight of at least one glycerol ether of the formula arba or a mixture of such glycerol ethers, and 7700-0.05, preferably 400-2, preferably 20-3 parts by weight of water. The glycerol ethers can be mixed in both the initial and subsequent drug production stages.

EXAMPLES Example (Solution for external use)

The hexadecylphosphocholine solution is obtained by dissolving hexadecylphosphocholine in the solvent labeled cascade 0.

Cascade 0 Preparation

1000 g of water, 1000 g of glycerol-1-n-propyl ether and 500 g of glycerol-1-n-nonyl ether are mixed in a suitable vessel.

Preparation of the solution

Add about 2 liters of cascade 0 and 180 g of hexadecylphosphocholine to a given vessel and dissolve with stirring. The volume is then increased to 3 1 by the addition of cascade 0. The density of the solution is 1.003 g / ml at 28 ° C.

This solution is aseptically filtered through a sterile membrane filter with pores of 0.2 gm diameter and dispensed into 10 ml dropper drops. One ml of solution contains 60 mg hexadecylphosphocholine.

example (Capsules)

Gelatin capsules containing 50 mg hexadecylphosphocholine 250 g hexadecyl phosphocholine 435.5 g lactose DAB 9 monohydrate, 241.5 g microcrystalline cellulose DAB 9 14 g talc DAB 9 7 g highly dispersible silica DAB 9 and 2 g magnesium st passes through a frame with 0.8 mm diameter holes and 30 min. homogenize in a given mixer. This capsule weight is dosed into a size 2 capsule by a 190 mg capsule filling machine.

Each capsule contains 50 mg hexadecylphosphocholine.

example (Tablets)

Hexadecylphosphocholine tablets containing 100 mg of 300 g of hexadecylphosphocholine and 600 g of lactose monohydrate DAB 9 are passed through holes of 0.8 mm diameter, mixed in a fluid bed granulator and granulated with 180 g of 10% gelatin solution. This granulate of 82.8 g of microcrystalline cellulose DAB 9, 120 g of corn starch, 16.8 g of talc and 2.4 g of magnesium stearate is passed through a 0.8 mm diameter grating. The resulting tablet mass is compressed into 380 mg and 10 mm diameter tablets.

Each tablet contains 100 mg hexadecylphosphocholine.

Claims (2)

DEFINITION OF INVENTION 1. For compounds of general formula I: R - Y - ΡΟ ₂ θ - X - Ri (I) wherein: R is a saturated or unsaturated hydrocarbon radical having from 12 to 24 carbon atoms which may be substituted by halogen, or R is -CH2-CHR3-CH2-. A group Z-R4 wherein R ₃ is an alkoxy group of C ₁ -C ₆ or an alkoxymethyl group of C ₁ -C ₆ , Z is oxygen or sulfur and R ₄ is a alkyl of C ₁ -C ₂₄ ; X is an oxygen atom or a group NH or NR ₂ wherein R ₂ is a saturated C 1 -C ₆ or unsaturated C 3 -C 6 alkyl radical; Y is an oxygen atom or an NH group; and R 1 is C ₁ -C ₈ alkyl or unsubstituted C ₂ -C ₈ alkyl substituted with one substituent such as halogen, amino, C 1 -C 8 alkylamino, C ₁ -C ₈ dialkylamino, C ₁ -C ₆ -trialkylamino, hydroxy, carboxyl, C ₃ -C 8 -cycloalkyl, or phenyl; and wherein R 1 may be, inter alia, 2-tetrabutyloxycarbonylaminoethyl, 2-tetrabutyloxycarbonylethyl, 2,3-isopropyldienedioxypropyl- (1), 2,3-dibenzyloxypropyl- (1), 1,3-dibenzyloxypropyl- (2) or 2,3- dihydroxypropyl- (1); and when X is NH, R 1 is 2,3-dihydroxypropyl (1), C ₁ -C 8 -alkyl or unsaturated C ₂ -C ₈ -alkyl substituted with such substituents as halogen, C 1 -C 8 -alkylamino, C 1 -C 8 -dialkylamino, C 1 -C 16-trialkylamino, hydroxyl, carboxyl, C ₃ -C 8 -cycloalkyl or phenyl, or the use of pharmaceutically acceptable salts of these compounds in the preparation of a medicament for the treatment of psoriasis. 2. A process for the preparation of a medicament for the treatment of psoriasis, comprising mixing one or more compounds of formula I according to claim 1 with alkyl glycerol of formula kurių: H ₂ C - O - Rs HC - O - Re (U) H ₂ C - O - H wherein one of the radicals R ₅ and R ₆ is an alkyl group having from 2 to 12 carbon atoms and the second radical is a hydrogen atom, or a mixture thereof with glycerol and water, per part by weight of a compound of formula I or in a mixture of 10000-7 parts by weight of an alkyl glycerol of formula arba or a mixture of alkyl glycerol and 7700-0.05 parts by weight of water, and / or with conventional carriers, excipients and / or diluents, and processing in the usual manner in the pharmaceutical field.