AU726572B2

AU726572B2 - Cosmetics or pharmaceutical compositions consisting of liposomes

Info

Publication number: AU726572B2
Application number: AU23880/99A
Authority: AU
Inventors: Jean-Luc Dubois
Original assignee: Hoechst Marion Roussel; Hoechst Marion Roussel Inc
Current assignee: Aventis Pharma SA
Priority date: 1994-02-16
Filing date: 1999-04-21
Publication date: 2000-11-09
Anticipated expiration: 2015-02-16
Also published as: AU2388099A

Description

P/00/011 Regulation 3.2

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

TO BE COMPLETED BY APPLICANT *:*Name of Applicant: HOECHST MARION ROUSSEL Actual Inventor(s): JEAN-LUC DUBOIS S::Address for Service: CALLINAN LAWRIE, 711 High Street, Kew, 3101, Victoria, Australia .:.Invention Title: "COSMETIC OR PHARMACEUTICAL COMPOSITIONS "CONSISTING OF LIPOSOMES" The following statement is a full description of this invention, including the best method of .:***erforming it known to me:- P Au, a Oo i1m/rnent9 .eceive,' onr o- Barcn Nx

I

15/4/199CF10335.CS0,1 Cosmetic or pharmaceutical compositions consisting of liposomes.

The present invention relates essentially to cosmetic or pharmaceutical compositions consisting of liposomes which contain an active compound.

The invention also relates to the preparation of cosmetic and pharmaceutical compositions, in particular dermatological compositions. Moreover, the composition described can be used as the basic substance for the preparation of medicaments.

A quite significant number of cosmetic or pharmaceutical preparations containing different active ingredients currently exist on the market. Also cosmetic and pharmaceutical compositions which contain vesicles of liposome type are well known, for example from Patents FR-A 2627385 or from EP-A 342100.

The present invention relates to cosmetic or pharmaceutical compositions consisting of liposomes which contain as active ingredient at least one compound of formula 25 I 2

CHCH

3 y C 2 30 in which:

R

1 represents a cyano or nitro radical or a halogen atom, R represents a trifluoromethyl radical or a halogen atom, the group is chosen from the radicals 35 X R R3 and -2in which X represents an oxygen or sulphur atom and R 3 is chosen from the following radicals: a hydrogen atom, alkyl, alkenyl, alkynyl, aryl or arylalkyl radicals having at most 12 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from the following radicals: hydroxy, halogen, mercapto, cyano, acyl or acyloxy having at most 7 carbon atoms, aryl, O-aryl, O-aralkyl, S-aryl in which the aryl radical containing at most 12 carbon atoms is optionally substituted and the sulphur atom is optionally oxidized in the form of the sulphoxide or sulphone, free, esterified, amidified or salified carboxy, amino, mono or dialkylamino or a heterocyclic radical having 3 to 6 members and containing one or more heteroatoms chosen from sulphur, oxygen or nitrogen atoms, the alkyl, alkenyl or alkynyl radicals being moreover optionally interrupted by one or more oxygen, nitrogen or sulphur atoms optionally oxidized in the form of the sulphoxide or sulphone, the aryl and aralkyl radicals being moreover optionally substituted by a halogen atom, by an alkyl, alkenyl or alkynyl, alkoxy, alkenyloxy, alkynyloxy or trifluoromethyl radical, trialkylsilyl radicals in which the linear or branched alkyl radical contains at most 6 carbon atoms, acyl or acyloxy radicals containing at most 7 carbon atoms, Y represents an oxygen or sulphur atom or a -NH radical.

The active compounds were described for example in the European Patent Application EP-A 494819. Moreover the European Patent Application EP-A 0 580 459 presents compounds of this type.

Preferably, the liposome is a phospholipid having a molecular weight between 777 and 790, a transition temperature between 45°C and 60°C and consisting of more than 90% phosphatidyl choline.

SThe cosmetic or pharmaceutical compositions preferably contain a 301 product of formula in which X represents an oxygen atom, Y represents an 17/2/99CF10335.SPE,2 oxygen atom, R 2 represents a halogen atom or a trifluoromethyl radical and R, represents a nitro radical, a halogen atom or a cyano radical and R 3 represents a hydrogen atom or an alkyl radical having at most 4 carbon atoms optionally substituted by a hydroxy or methoxy radical.

O 17/2/99CP10335.SPE,2 Preferably, a compound of formula NC -N -(CH 2 4 -OH r

CH

3

CF

3 0 CH is used as active compound.

The definitions used above can have the following values: By alkyl having at most 12 carbon atoms is meant for example the following linear or branched values: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertbutyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl, heptyl, octyl, decyl, undecyl, dodecyl.

Alkyl radicals are preferred having at most 6 carbon atoms and in particular the following radicals: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, linear or branched pentyl, linear or branched hexyl.

By alkenyl having at most 12 and preferably 4 carbon atoms is meant for example the following values: vinyl, allyl, 1-propenyl, butenyl, pentenyl, hexenyl.

Among the alkenyl values, the allyl values or butenyl values are preferred.

S 30 By alkynyl having at most 12 and preferably 4 carbon atoms is meant for example the following values: ethynyl, propargyl, butynyl, pentynyl or hexynyl.

Among the alkynyl values, the propargyl value is preferred.

By aryl is meant the carbocyclic aryl radicals such as the phenyl or the naphthyl or heterocyclic aryl radicals with 5 or 6 members containing one or more heteroatoms preferably chosen from oxygen, sulphur and nitrogen. Among the heterocyclic aryls with 5 members, the following radicals can be mentioned: furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, pyrazolyl, isoxazolyl.

Among the heterocyclic aryls with 6 members, the pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl radicals can be mentioned.

Among the condensed aryl radicals, the indolyl, benzofurannyl, benzothienyl, quinolinyl radicals can be mentioned.

The phenyl radical is preferred.

By arylalkyl is meant the radicals resulting from the combination of the alkyl radicals mentioned previously, optionally substituted, and the aryl radicals also mentioned above, optionally substituted.

The benzyl, phenylethyl or triphenylmethyl radicals are preferred.

By halogen is meant, of course, fluorine, chlorine, bromine or iodine atoms.

The fluorine, chlorine or bromine atoms are preferred.

As particular examples of alkyl radicals substituted by one or more halogens, the following radicals can be mentioned: monofluoro, chloro, bromo or iodomethyl, difluoro, dichloro or dibromomethyl, trifluoromethyl.

25 As particular examples of substituted aryl or arylalkyl radicals, there can be mentioned those in which the phenyl radical is substituted by a fluorine atom or by a methoxy or trifluoromethyl radical.

By acyl radical is preferably meant a radical having 30 at most 7 carbon atoms such as the acetyl, propionyl, butyryl or benzoyl radical, but it can also represent a valeryl, hexanoyl, acryloyl, crotonoyl or carbamoyl radical: the formyl radical can also be mentioned.

By acyloxy radical is meant radicals in which the acyl radicals have the meaning indicated above and for example the acetoxy or propionyloxy radicals.

By esterified carboxy is meant for example the radicals such as the alkyloxycarbonyl radicals for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyl or tertbutyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl or cyclohexyloxycarbonyl.

There can also be mentioned radicals formed with easily cleavable ester remainders such as methoxymethyl, ethoxymethyl radicals; acyloxyalkyl radicals such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl; alkyloxycarbonyloxy alkyl radicals such as methoxycarbonyloxy methyl or ethyl radicals, isopropyloxycarbonyloxy methyl or ethyl radicals.

A list of such ester radicals can be found for example in the European Patent EP 0,034,536.

By amidified carboxy is meant the radicals of

R

6 -CON type in which the radicals R 6 and R 7 identical R7 or different, represent a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl radicals.

R

Among the -N radicals, the amino, mono or

R

7 dimethylamino radicals are preferred.

R

6 The N radical can-also represent a heterocycle .R Swhich may or may not contain an additional heteroatom. The S"following radicals can be mentioned: pyrrolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidyl, indolyl, piperidino, o 30 morpholino, piperazinyl. The piperidino or morpholino radicals are preferred.

By salified carboxy is meant the salts formed for example with an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. There can also be mentioned S 35 the salts formed with organic bases such as methylamine, propylamine, trimethylamine, diethylamine, triethylamine.

The sodium salt is preferred.

By alkylamino radical is meant linear or branched methylamino, ethylamino, propylamino or butyl, amino radicals. The alkyl radicals having at most 4 carbon atoms are preferred, the alkyl radicals can be chosen from the alkyl radicals mentioned above.

By dialkylamino radical is meant for example the dimethylamino, diethylamino, methylethylamino radicals. As before, the alkyl radicals having at most 4 carbon atoms, chosen from the above-indicated list, are preferred.

By heterocyclic radical containing one or more heteroatoms is meant for example the saturated heterocyclic, monocyclic radicals such as oxirannyl, oxolannyl, dioxolannyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl or morpholinyl.

By alkyl, alkenyl or alkynyl radicals optionally interrupted by a heteroatom chosen from sulphur, oxygen or nitrogen atoms is meant radicals containing within their structure one or more of these identical or different atoms, these heteroatoms obviously not being able to be situated at the end of the radical. There can be mentioned for example alkoxyalkyl radicals such as methoxymethyl, methoxyethyl, methoxypropyl and methoxybutyl or also alkoxy alkoxyalkyl radicals such as methoxyethoxymethyl.

By trialkylsilyl radical in which the alkyl radical S9 contains at most 6 carbon atoms is meant for example, thetrimethylsilyl, triethylsilyl, (1,1-dimethylethyl) dimethylsilyl radicals.

When the products of formula contain an amino radical which can be salified by an acid it is understood that these acid salts can also be used. For example, the 30 salts formed with hydrochloric or methanesulphonic acids can be mentioned.

The preparation process for the products of general .o formula as defined above is described by EP-A 494819.

The cosmetic or pharmaceutical compositions of the present invention advantageously contain from 0.001 to about 20% by weight, preferably from 0.01 to 10% by weight, of the active compound or compounds of formula relative to the weight of the total composition.

The compositions consisting of liposomes can be presented in various forms, for example in the form of a gel, cream, milk, balm or lotion.

The active ingredient is at least partly incorporated in vesicles of liposome type, in particular in a proportion of more than 20%, preferably in a proportion of more than 50%, and especially more than In principle, the compositions containing liposomes can be prepared according to the following technique, which was described in FR-A 2627385: The active ingredients are first of all prepared for example, in the form of an aqueous solution, if they are soluble in water.

The vesicles of the liposomes are constituted by a lipid phase containing at least one of the following substances: phospholipids, of natural or synthetic origin, phospholipids combined with glycerides, phospholipids combined with glycolipids, cerebrosides, sphingolipids, cephalins, phosphoaminolipids, cerebroglucosides, gangliosides, 25 optionally combined with natural or synthetic cholesterol.

This lipid phase is dissolved in a volatile solvent, which varies according to the type of substance chosen, for S"example an organic solvent such as chloroform or methanol.

The lipid solution obtained is placed in a flask then evaporated under reduced pressure in a rotary evaporator until a film is formed on the walls of the flask.

Then the aqueous solution of the active ingredients to be encapsulated is added under constant agitation, and in this way a suspension is obtained which is then subjected to ultrasound.

Thus a suspension of liposome-type vesicles is obtained incorporating at least in part the active ingredient in aqueous solution.

The encapsulation of the active ingredients thus achieved involves optimizing their cosmetodynamic activity.

The topical use of an active ingredient encapsulated in liposomes allows the active ingredient to be concentrated in the sebaceous glands, in order to obtain a higher and longerlasting concentration in the epidermis and in the dermis in vivo, than that obtained by standard topical applications, and finally the systemic effect to be limited by minimizing the passage of the active ingredient into the blood circulation; the side effects of the products are therefore reduced.

The percutaneous penetration of the active ingredient therefore depends on the active compound and the method by which the liposomes are produced.

The preparation of the compositions containing liposomes using the lipid phase dissolved in a volatile solvent has disadvantages because traces of solvent can still be found in the final composition.

Also a subject of the invention is a method for preparing liposomes which does not use organic solvents and which produces satisfactory results as far as percutaneous penetration of the active ingredient is concerned.

The invention relates to a preparation process for a cosmetic or pharmaceutical composition consisting of 25 liposomes, characterized in that an emulsion or aqueous suspension is prepared containing an active compound (for example, a compound of formula and one or more lipid S"compounds and optionally additives such as a pH buffer, an anti-oxidant or an antiseptic, and in that the emulsion or 30 the suspension is agitated at a temperature comprised between 400 and 80 0 C, preferably between 400 and 750C, especially between 600 and 70 0 C, and in that a process for reducing the size of the liposomes is then carried out. Preferably, a solid dispersion is prepared hot, containing the active 35 compound, one or more lipid compounds and optionally additives and this solid dispersion is placed in water. This process is carried out without using organic solvents.

The invention has then particularly for subject a process as defined above characterized in that a mixture of lipidic constituents comprising one or more active principles, the phospholipids and the preservatives is prepared beforehand, which is then heated at a temperature comprised between 40' and 80'C up to melting, then in that the mixture thus obtained is placed under agitation in presence of the hydrophylic compounds comprising the pH buffer, one or more antiseptics for obtaining the solution of liposomes which is submitted to a process of size reduction.

The originality of the invention also resides in the fact that the active ingredient has a low melting point of about 100 0 C and that this active ingredient is dissolved in or is soluble in the phospholipid or the phospholipid mixture at low temperature (for example between 500 and 70 0

C).

Moreover, this low temperature minimizes the oxidation or the degradation of the phospholipids and corresponds to the optimal temperature for emulsification of the phospholipids in water or in the pH buffer.

The process according to the invention can be carried out with various active ingredients but preferably a compound of formula as defined above and quite particularly the compound of formula N. 2 J

^H,

30 30 _0H is used as active ingredient.

Very useful compositions are obtained by using the method described.

As lipid compound, a natural, semi-synthetic or synthetic phospholipid is used, for example Lipoid E 100.35, Lipoid EPC 3 or Lipoid SPC 3, hydrogenated or not (which are marketed by the Societ6 Diet&tique Francaise de Formulation et de Frabrication, 24, Avenue Hoche, 75008 Paris, France).

The three products have a molecular weight between 777 and 790, a transition temperature between 450 and 60 0 C and consist of more than 90% egg phosphatidylcholine or soya phosphatidylcholine.

As pH buffer, a phosphate buffer (pH 7) can for example be used.

As anti-oxidant, a-tocopherol acetate or atocopherol can be used (for example at a concentration comprised between 0.1 and preferably between 0.5 and 2% of the weight of the lipid compounds).

As antiseptic, generally known compounds are used such as for example the parahydroxybenzoates of propyl, ethyl or methyl at a concentration of 0.01 to 0.5% and preferably between 0.05 and or also Bronopol at a concentration of 0.1%.

For the preparation of medicaments, other additives can also be added to the described compositions. For example for the preparation of the gel, carboxymethylcellulose (Blanose®) or another commonly-used gelling agent is added slowly to the liposome suspension under agitation at ambient temperature.

Gels with 0.75%, 1% and 1.25% of Blanose® are obtained.

According to the process described, a molar ratio of phospholipid/active ingredient of between 1.0 and 20.0 but 25 preferably between 5.5 and 15.0, especially between 8 and 12 for the compound of formula as active ingredient, is normally used.

The percentage of encapsulation of the active compound normally increases with the molar ratio of lipid/active 30 compound.

The concentration of active ingredient in the aqueous suspension depends on the concentration of phospholipids.

Normally, a concentration of more than 10 mmol of phospholipids per litre of aqueous phase is used, preferably between 30 and 400 mmol/l, especially between 60 and 300 Smmol/1.

In principle, the various methods for reducing the size of the liposomes are applicable. Preferably, a microfluidizer is used (see S. Vemuri et al., "Large-scale Production of Liposomes by a Micro-fluidizer", Drug Develop.

Ind. Pharm.; 1990; 16,15; 2243-2256). In the interaction chamber of the micro-fluidizer, two flows of the liposome suspension enter under collision under high pressure and at great speed. The result is a reduction in the size of the vesicles.

The temperature during the fusion, emulsification and passage into the micro-fluidizer must normally be greater than the transition temperature of the lipid compounds.

Preferably, the preparation process according to the invention is characterized in that the emulsion or the suspension is agitated at a temperature comprised between and 75 0

C.

The liposomes obtained using the micro-fluidizer have sizes which are identical to or smaller than those obtained by the methods using ultrasound (see E. Mayhew et al., "A practical method for the large scale manufacture of liposomes", Pharmaceutical Manufacturing, 1985, 8, 18-22).

The emulsion or the suspension containing the liposomes can pass through the micro-fluidizer once or several times, normally they are passed through the microfluidizer 1 to 6, preferably 2 to 5 times, because after this no significant changes in the size of the liposomes are 25 observed.

tThe preparation process according to the invention is therefore characterized in that one or more passes of the emulsion or the suspension through a micro-fluidizer is used as the process for reducing the size of the liposomes.

The preparation process for the cosmetic or pharmaceutical composition is easy to reproduce and can be carried out on an industrial scale. Moreover, preparations with a high content of phospholipids and active ingredient can be obtained.

35 The pharmaceutical preparations can be used as medicaments for example in dermatology, because there is optimal penetration of the active ingredient through the skin.

12 According to the invention, the liposomes containing the active ingredient localize the penetration into the epidermis and into the sebaceous glands while minimizing passage into the circulatory system.

The compositions of the present invention can also be used as medicaments for the treatment of adenomas and neoplasias of the prostate, for combating benign hypertrophy of the prostate, for the treatment of benign or malignant tumours the cells of which contain in particular androgen receptors. There can in particular be mention mainly cancers of the breast, the skin and the ovaries but also cancers of the bladder, the lymphatic system, the kidney, the liver.

Moreover, the compositions can also be used in the treatment of hirsutism, acne, seborrhea, androgenic alopecia, hyperpilosity and in cosmetology.

The compounds can therefore be used in dermatology: they can be used alone or in combination. They can be combined in particular with an antibiotic product such as a derivative of azelaic or fusidic acid, erythromycin or with a derivative of the retinoids for the treatment of acne, or with a 5a-reductase inhibitor such as (5a,17p)-l,ldimethylethyl 3-oxo 4-aza-androst-l-ene 17-carboxamide (or Finasteride, Merck, llth Ed.) or azelaic acid or a blocking agent of the androgen receptors for the treatment of acne, 25 alopecia or hirsutism, or with a product stimulating hair growth such as Minoxidil for the treatment of alopecia.

The compositions can also be used in the veterinary domain.

The compositions containing radioactive products can 30 also be used in diagnostics as specific markers of the androgen receptors. As radioactive products, there can be used, for example, active ingredients marked with tritium, with carbon 14 or also with iodine 125.

EXAMPLE 1: preparation of the active ingredient: 4-(4,4- 35 dimethyl 2,5-dioxo 3-(4-hydroxy butyl) 1-imidazolidinyl) 2- (trifluoromethyl) benzonitrile a) Condensation 600 mg of 4 4 4 -dimethyl-2,5-dioxo-l-imidazolidinyl)-2- (trifluoromethyl)-benzonitrile obtained as in Example 8 of European Patent Application No. 0,494,819 in 5 cm 3 of dimethylformamide is added to a suspension of 104 mg of sodium hydride in 0.8 cm 3 of dimethylformamide, while maintaining the temperature below 20 0 C. After agitation for minutes, 445 mg of 4-chloro t-butyl dimethylsilylether and 300 mg of sodium iodide are added. The whole is heated for 16 hours at 50 0 C, cooled down to ambient temperature, 87 mg of sodium hydride then a further 400 mg of chlorinated ether and 267 mg of sodium hydride are added, and heating is continued for another hour. The reaction medium is returned to ambient temperature, poured into 60 cm 3 of water containing 600 mg of monopotassium phosphate. Extraction is carried out with ether, the organic phase is washed with water, dried and the solvent is evaporated off. The residue is chromatographed on silica (eluant: methylene chloride acetone 526 mg of product is collected, used as it is for the following stage.

b) Cleavage The product obtained above is mixed with 5 cm 3 of methanol and 1.5 cm 3 of 2N hydrochloric acid. The mixture is agitated for 40 minutes at ambient temperature, poured into 30 cm 3 of water, extracted with methylene chloride, the organic phase is washed with water, dried and the solvent is 25 evaporated off. After chromatographing the residue on silica (eluant: methylene chloride acetone the fractions with Rf 0.15 are collected and after recrystallization from isopropyl ether, 307 mg of expected product is obtained.

M.p. 102-103 0

C.

Preparation of the 4-chloro t-butyl dimethylsilylether used at the start of the example.

9.9 cm 3 of 4-chloro 1-butanol and 24.3 g of imidazole are mixed under agitation in 50 cm 3 of tetrahydrofuran. 2.82 g of terbutyldimethylsilyl chloride in *i 35 20 cm 3 of tetrahydrofuran is added drop by drop at a temperature below 20 0 C, agitation is carried out for 18 hours at ambient temperature, followed by separating, rinsing with tetrahydrofuran and the solvent is eliminated under reduced pressure. The residue is purified by chromatography on silica (eluant: cyclohexane ethyl acetate and 17.5 g of expected product is collected.

EXAMPLE 2: the following active ingredients are described and prepared as indicated in European Patent Applications EP-A 494819 and EP-A 0580459: (1,1-dimethyl) ethyl 3-(4-cyano 3-(trifluoromethyl) phenyl 5-dimethyl 2, 4-dioxo 1-imidazolidineacetate, cyclopentyl 3-(4-cyano 3-(trifluoromethyl) phenyl) dimethyl 2,4-dioxo 1-imidazolidineacetate, ethyl 3-(4-cyano 3-(trifluoromethyl) phenyl) 2, 4-dioxo 1-imidazolidinebutanoate, 3-(4-cyano 3-(trifluoromethyl) phenyl) 5,5-dimethyl 2,4dioxo 1-imidazolidinebutanoic acid, (1,1-dimethyl) ethyl 3-(4-cyano 3-(trifluoromethyl) phenyl) 5-dimethyl 2, 4-dioxo 1-imidazolidinebutanoate, cyclopentyl 3-(4-cyano 3-(trifluoromethyl) phenyl) dimethyl 2, 4-dioxo 1-imidazolidinebutanoate, 4-(4,4-dimethyl 2,5-dioxo 3-(2-((4-fluorophenyl) thia) ethyl) 1-imidazolidinyl 2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 2,5-dioxo (4-f luorophenyl) sulphonyl) ethyl) 1-imidazolidinyl 2- (trifluoromethyl) benzonitrile, -4-(4,4-dimethyl 2,5-dioxo (4-f luorophenyl) suiphinyl) *.ethyl) 1-imidazolidinyl 2- (trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 2,5-dioxo 3-((3-methoxyphenyl) methyl) 1imidazolidinyl 2- (trifluoromethyl) benzonitrile, -4-(4,4-dimethyl 2,5-dioxo 3-(2-(4-morpholinyl) ethyl) 1imidazolidinyl 2- (trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 3-(2-hydroxyethyl) 5-imino 2-thioxo 1imidazolidinyl) 2-(trifluoromethyl) benzonitrile, -4-(4,4-dimethyl 3-(2-hydroxyethyl) 5-oxo 2-thioxo 1imidazolidinyl) 2- (trifluoromethyl) benzonitrile, -4-(4,4-dimethyl 3-(2-hydroxyethyl) 5-imino 2-thioxo 1imidazolidinyl) 2-(trifluoromethyl) 5- 3 H benzonitrile, 4-(4,4-dimethyl 3-(2-hydroxyethyl) 5-oxo 2-thioxo 1imidazolidinyl) 2-(trifluoromethyl) 5- HI benzonitrile, 4-(4 ,4-dimethyl 3-(3-hydroxypropyl) 5-imino 2-thioxo 1imidazolidinyl) 2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 3-(3-hydroxypropyl) 5-oxo 2-thioxo 1imidazolidinyl) 2-(trifluoroethyl) berizonitrile, 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-thioxo 1imidazolidinyl) 2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 2-thioxo 1imidazolidinyl) 2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 3-(2-methoxyethyl) 5-imino 2-thioxo 1imidazolidinyl) 2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 3-(2-methoxyethyl) 5-oxo 2-thioxo 1imidazolidinyl) 2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 3-Ci-methylethyl) 5-imino 2-thioxo 1imidazolidinyl) 2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 3-(1-methylethyl) 5-oxo 2-thioxo 1imidazolidinyl) 2- (trifluoromethyl) benzonitrile, 3-(3,4-dichlorophenyl 5,5-dimethyl 1-(3-hydroxypropyl) 4imino 2-imidazolidine thione, 3-(3 ,4-dichlorophenyl 5, 5-diinethyl 1-(3-hydroxypropyl) 2thioxo 4-imidazolidinone, 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-thioxo 1imidazolidinyl) 2-(trifluoromethyl) (5- 3 H) benzonitrile, 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 2-thioxo 1imidazolidinyl) 2-(trifluoromethyl) (5- 3 H) benzonitrile, -4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-thioxo 1imidazolidinyl) 2-(trifluoromethyl) benzo (14C) nitrile, 4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-oxo 2-thioxo 1imiazoidiyl)2-(trifluoromethyl) benzo (14C)ntie -4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-oxo 1imidazolidinyl) 2- (trifluoromethyl) (5- 3 H) benzonitrile, 4-(4,4-dimethyl 2,5-dioxo 3-(4-hydroxybutyl) 1- 30 imidazolidinyl) 2-(trifluoromethyl) (5- 3 H) benzonitrile, -4-(4,4-dimethyl 3-(4-hydroxybutyl) 5-imino 2-oxo 1imidazolidinyl) 2-(trifluoromethyl) benzo (14C) nitrile, -4-(4,4-dimethyl 2,5-dioxo 3-(4-hydroxybutyl) 1imidazolidinyl) 2-(trifluoromethyl) benzo (14C nitrile, 35~ 4-(2,5-dioxo 4,4-dimethyl 3-(4-triphenylmethoxybutyl) 1imidazolidinyl) 2-(trifluoromethyl) benzonitrile, 4-(2,5-dioxo 4,4-dimethyl 3-(4-phenylmethoxybutyl) 1imidazolidinyl) 2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl-2,5-dioxo 3-(4-methoxybutyl) 1imidazolidinyl] 2-(trifluoromethyl) benzonitrile, 4-[3-(4-chlorobutyl) 4,4-dimethyl 2,5-dioxo 1imidazolidinyl] 2-(trifluoromethyl) benzonitrile, 4-[3-(4-[(methylsulphonyl) oxy] butyl] 4,4-dimethyl dioxo 1-imidazolidinyl] 2-(trifluoromethyl) benzonitrile, 4-(3-acetyl 4,4-dimethyl 2,5-dioxo 1-imidazolidinyl) 2- (trifluoromethyl) benzonitrile, 4-(3-benzoyl 4,4-dimethyl 2,5-dioxo 1-imidazolidinyl) 2- (trifluoromethyl) benzonitrile, 4-[3-[dimethyl (1,1-dimethylethyl) silyl] 4,4-dimethyl dioxo 1-imidazolidinyl] 2- (trifluoromethyl) benzonitrile, l-(4-nitro-3-(trifluoromethyl) phenyl) -3,4,4-trimethyl-2,5imidazolidinedione, 5,5-dimethyl-l-ethyl-3-(4-nitro-3-(trifluoromethyl) phenyl) 4-imidazolidinedione, 5,5-dimethyl-3-(4-nitro-3-(trifluoromethyl) phenyl) -1propyl-2, 4-imidazolidinedione, 5,5-dimethyl-1-(1--methyl ethyl)-3-(4-nitro-3-(trifluoromethyl) phenyl) 4-imidazolidinedione, 5,5-dimethyl-3-(4-nitro-3-trifluoromet hyl) phenyl) propenyl) -2 ,4-imidazolidinedione, 5-dimethyl-3-(4-nitro-3-(trifluoromethyl) phenyl) -1methyl phenyl-2, 4-imidazolidinedione.

4-(4,4-dimethyl-5-imino-2-oxo-l-imidazolidinyl)-2- (trifluoromethyl) -benzonitrile, 4-dimethyl-2, 5-dioxo-1-imidazolidinyl) -2-(trifluoromethyl) -benzonitrile, -3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-2,4- 30 dioxo-1-imidazolidine acetic acid, ethyl 3-(4-cyano-3-(trifluoromethyl) phenyl) 2, 4-dioxo-l-imidazolidine acetate, 4-(5-imino-2-thioxo-3,4,4-trimethyl-l-imidazolidinyl)-2- (trifluoromethyl) -benzonitrile, 4-(5-oxo-2-thioxo-3,4,4-trimethyl-1-imidazolidinyl)-2- S. (trifluoromethyl) -benzonitrile, 4-(2,5-dithioxo-3,4,4-trimethyl-1-imidazolidinyl)-2-(trifluoromethyl) -benzonitrile, 4-(4,4-dimethyl-5-imino-2-thioxo-1-imidazolidinyl)--2-(triifluoromethyl) -benzonitrile, 4-(4,4-dimethyl-5-oxo-2-thioxo-1-imidazolidinyl)-2-(triifluoromethyl) -benzoriitrile, 5,5-dimethyl-3-(4-nitro-3-(trifluoromethyl) phenyl) -1pentyl-2, 4-imidazolidinedione, 5,5-dimethyl-3-(4-nitro-3-(trifluoromethyl) phenyl)-1nonyl-2, 4-imidazolidinedione, 4-(3,4,4-trimethyl-2,5-dioxo 1-imidazolidinyl) 2- (trifluoromethyl) berizonitrile, 4-(5-thioxo-2-oxo-3,4,4-trimethyl-l-imidazolidinyl) 2- (trifluoromethyl) -benzonitrile (product 4-(5-oxo-2thioxo-3 ,4 ,4-trimethyl 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile (product 5-dithioxo-3 ,4,4-trimethyl-1imidazolidinyl) 2-(trifluoromethyl)-benzonitrile (product C), 4-(4,5-dihydro 4,4-dimethyl 2-(methylthio) 5-oxo liiimidazol-1-yl) 2-(triifluoromethyl) -benzonitrile, 4-[4,5-dihydro 4,4-dimethyl 5-oxo 2-[(phenylmethyl) thio] 1H-imidazol-1-yl] 2-(trifluoromethyl)-benzonitrile, 4-(4,4-dimethyl 3-(2-hydroxyethyl) 5-imino 2-thioxo 1imidazolidinyl] 2- (trifluoromethyl) benzonitrile, 4-[4,4-dimethyl 3-(2--hydroxyethyl) 5-oxo 2-thioxo 1imidazolidinyl] 2-(trifluoromethyl) benzonitrile (Product A) and 4-(4,4-dimethyl 2,5-dioxo 3-(2-mercaptoethyl) 1imidazolidinyl] 2-(trifluoromethyl) benzonitrile (Product B), 4-(4,4-.dimethyl 2,5-dioxo 3-ethyl 1-imidazolidinyl) 2- (trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 2,5-dioxo 3-(2-propenyl) 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 2,5-dioxo 3-(phenylmethyl) 1imidazolidinyl) 2-(triifluoromethyl) benzonitrile, -4-[4,4-dimethyl 2,5-dioxo (4-f luorophenyl) methyl] 1imidazolidinyl] 2-(triifluoromethyl) benzonitrile, -4-14,4-dimethyl 2,5-dioxo 3-[(4-methoxyphenyl) methyl] 1imidazolidinyl] 2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 2,5-dioxo [4-(trifluoromethyl) phenyl] methyl] 1-imidazolidinyl] 2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 2,5-dioxo 3-(2-epoxyiethyl) 1imidazolidinyl] 2-(trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 2,5-dioxo 3-propyl-lH-ilnidazolidinyl) 2- (trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 2,5-dioxo 3-(1-methylethyl) 1imidazolidinyl] 2- (trifluoromethyl) benzonitrile, 4-[4,5-dihydro 4,4-dimethyl 2-(nonylthio) 5-oxo 1Himidazol-l-yl] 2-(trifluoromethyl) benzonitrile, 4-[4,5-dihydro 4,4-dimethyl 2-((3-hydroxypropyl) thio] oxo 1H-imidazol-1-yl] 2-(trifluoromethyl) benzonitrile, ethyl (Ij-(4-cyano 3-(trifluoromethyl) phenyl] 4,4-dimethyl 5-oxo 1H-imidazol-2-yl] thio] acetate, 4-(4,4-dimethyl 3-ethyl 5-imino 2-thioxo 1-imidazolidinyl) 2- (trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 5-imino 3-pentyl 2-thioxo 1-imidazolidinyl) 2- (trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 3-ethyl 5-oxo 2-thioxo 1-imidazolidinyl) 2- (trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 5-oxo 3-pentyl 2-thioxo 1-imidazolidinyl) 2- (trifluoromethyl) benzoriitrile, 4-(4,5-dihydro 4,4-dimethyl 2-(methylthio) 5-thioxo lHimidazol-l-yl] 2- (trifluoromethyl) benzonitrile, 4-(4,5-dihydro 4,4-dimethyl 2-[(phenylmethyl) thio] thioxo 1H-imidazol-1-yl] 2-(trifluoromethyl) benzonitrile, -3-[4-cyano 3-(trifluoromethyl) phenyl] 5,5-dimethyl 2,4dioxo N-methyl N-(l-methylethyl) l-imidazoljidine acetamide, 4,-[4,4-dimethyl 2,5-dioxo 3-(2-hydroxyethyl) 1-imidazolidinyl] 2-(trifluoromethyl) benzonitrile, 4-114, 4-dimethyl 2, 5-dioxo 3-(3-hydroxypropyl) 1-imidazolidinyl] 2-(trifluoromethyl) benzonitrile, 4-(3-[2-(acetyloxy) ethyl] 4,4-dimethyl 2,5-dioxo 1-imidazolidinyl] 2-(trifluoromethyl) benzonitrile, -4-[4,4-dimethyl 2,5-dioxo 3-(5-hydroxypentyl) 1-imidazolidinyl] 2-(trifluoromethyl) benzonitrile, -4-[4,4-dimethyl 2,5-dioxo 3-(2-methoxyethyl) 1-imidazo- C 35 lidinyl] 2-(trifluoromethyl) benzonitrile, -4-(4,4-dimethyl 2,5-dioxo 3-(cyanomethyl) 1-imidazolidinyl] 2- (trifluoromethyl) benzonitrile, 4-(4,4-dimethyl 2,5-dioxo (1,3-dioxalan-2-yl) methyl] 1imidazolidinyl] 2-(trifluoromethyl) benzonitrile, 4-[4,4-dimethyl 2,5-dioxo 3-(2-chloroethyl) 1-imidazolidinyl] 2-(trifluoromethyl) benzonitrile, 1-(3,4-dichlorophenyl) 5-imino 3,4,4-trimethyl 2-imidazolidine thione, -3-(3,4-dichlorophenyl) 2-thioxo 1,5,5-trimethyl 4-imidazolidinone, 3-(3,4-dichlorophenyl) 3,5-dihydro 5,5-dimethyl 2-(methylthio) 4H-imidazol-4-one, 1-(3,4-dichlorophenyl) 3,4,4-trimethyl dithione, 1-(4-chloro 3-(trifluoromethyl) phenyl] 4,4-dimethyl 2thioxo 1-(4-chloro 3-(trifluoromethyl) phenyl] 4,4-dimethyl imino 2-imidazolidine thione, 3-(3 ,4-dichlorophenyl) 3 ,5-dihydro 5, 5-dimethyl 2- [(phenylmethyl) thio] 4H-imidazol-4-one.

EXAMPLE 3: Preparation process for a composition consisting of liposomes 0.13 g of a-tocopherol is added to a mixture containing g of the active ingredient 4-(4,4-dimethyl 2,5-dioxo 3- (4-hydroxybutyl) 1-imidazolidinyl) 2-(trifluoromethyl) benzonitrile and 10.77 g of phospholipid (lipoid E.100.35).

The mixture is heated by agitating at a temperature greater than the transition temperature of the phospholipid, preferably at 60 0 C-70 0 C. The transition temperature of the phospholipid chosen is preferably about 60 0

C.

A solution is prepared which contains: 0.1 g of methyl para-hydroxybenzoate and 0.05 g of propyl para-hydroxybenzoate in 100 ml of pH 7 buffer solution heating to a high temperature 100 0

C).

This solution is added to the mixture of the active ingredient and phospholipid.

a-tocopherol acetate or a-tocopherol is added to this solution. Agitation is carried out until the mixture is homogeneous.

This solution is passed through a micro-fluidizer (1 to 6 passes, pressure 15 to 140 MPa). The preparation can be used as it is or it can be incorporated with a gelling agent such as hydroxypropyl cellulose (Blanose T6F) at the rate of 1% or any other gelling agent.

The final composition contains lipsomes whose size is comprised between 40 and 120 nm.

The composition can be used for the treatment of illnesses and in cosmetology or dermatology.

EXAMPLE 4: Using a preparation similar to that described in Example 3, compositions are prepared consisting of liposomes which contain the active compounds of Example 2.

Where the terms Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of one or more other feature, integer, step, component or group thereof.

S This is a divisional application of Australian Patent Application No. 12277/95, the 20 disclosure of which is incorporated herein by way of reference.

Claim 1 of Australian Patent No. 701344 provides as follows: Cosmetic or pharmaceutical compositions consisting ofliposomes which contain an active compound, wherein the liposomes contain as active ingredient at least one compound of 25 formula

(I)

R C R Y C H 3

&I

s Y

PA--:

11/09/00,documentl 1,20 in which

R

1 represents a cyano radical, a nitro radical or a halogen atom,

R

2 represents a trifluoromethyl radical or a halogen atom, the group is chosen from the radicals r' N Rz nd in which X represents an oxygen atom, Y represents an oxygen atom and R3 represents a hydrogen atom or an alkyl radical having at most 4 carbon atoms optionally substituted by a hydrogen or methoxy radical.

The subject matter of the claims of 701344 is hereby specifically disclaimed.

Subject to this *a e a S 11/09/0,documetll120

Claims

1. Cosmetic or pharmaceutical compositions consisting of liposomes which contain an active compound, wherein the liposomes contain as active ingredient at least one compound of formula (I) R 1 R, Y CH 3 in which: R, represents a cyano or nitro radical or a halogen atom, R 2 represents a trifluoromethy radical or a halogen atom, the group is chosen from the radicals S-R 3 and N RR 3 in which X represents an oxygen or sulphur atom and R 3 is chosen from the following radicals: a hydrogen atom, alkyl, alkenyl, alkynyl, aryl or arylalkyl radicals having at most 12 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from the following radicals: hydroxy, halogen, mercapto, cyano, acyl or :16 acyloxy having at most 7 carbon atoms, aryl, O-aryl, O-aralkyl, S-aryl in which the aryl radical containing at most 12 carbon atoms is optionally substituted and the sulphur atom is optionally oxidized in the form of the sulphoxide or sulphone, free, esterified, amidified or salified carboxy, amino, mono or dialkylamino or a heterocyclic radical consisting of 3 to 6 members and 11/2/99CF10335.SPE,21 -22- containing one or more heteroatoms chosen from sulphur, oxygen or nitrogen atoms, the alkyl, alkenyl or alkynyl radicals moreover being optionally interrupted by one or more oxygen, nitrogen or sulphur atoms optionally oxidized in the form of the sulphoxide or sulphone, the aryl and aralkyl radicals moreover being optionally substituted by a halogen atom, by an alkyl, alkenyl or alkynyl, alkoxy, alkenyloxy, alkynyloxy or trifluoromethyl radical, trialkylsilyl radicals in which the linear or branched alkyl radical contains at most 6 carbon atoms, acyl or acyloxy radicals containing at most 7 carbon atoms, Y represents an oxygen or sulphur atom or a NH radical.

2. Cosmetic or pharmaceutical compositions according to claim 1, in which in the product of formula X represents an oxygen atom, Y represents an oxygen atom, R 2 represents a halogen atom or a trifluoromethyl radical, R, represents a nitro radical, a halogen atom or a cyano radical and R 3 represents a hydrogen atom or an alkyi radical having at most 4 carbon atoms optionally 5 substituted by a hydroxy or methoxy radical.

3. Cosmetic or pharmaceutical compositions according to claim 1, in which the liposomes contain as active compound a compound of formula (I) -CH Crf o CHs

4. Cosmetic or pharmaceutical compositions according to any one of claims 1 to 3, wherein the liposome is a phospholipid. Cosmetic or pharmaceutical compositions according to claim 4 wherein the phospholipid has a molecular weight between 777 and 790, a transition temperature between 45°C and 60°C and consists of more than li/2/9CF10335.SPE,22 -23- phosphatidyl choline.

6. Preparation process for a cosmetic or pharmaceutical composition consisting of liposomes, wherein an emulsion or aqueous suspension is prepared containing as an active compound a compound of formula as defined in claim 1; one or more lipid compounds; and optionally additives and that the emulsion or the suspension is agitated at a temperature comprised between 40° and and that a process for reducing the size of the liposomes which comprises passing the emulsion or suspension through a micro-fluidizer, is then carried out.

7. Preparation process according to claim 6, wherein the optional additives include a pH buffer, an anti-oxidant or an antiseptic.

8. Preparation process according to claim 6 or claim 7, wherein a compound of formula 0

9. Preparation process according to any one of claims 6 to 8, wherein a 20 phosphatidyl choline. 99 S is used as active compound. 9 Preparation process according to any one of claims 6 to 8, wherein a phospholipid is used as the lipid compound. Preparation process according to claim 9, wherein the phospholipid used as the lipid compound has a molecular weight between 777 and 790, a transition temperature between 45-C and 60°C and consists of more than phosphatidyl choline.

11. Preparation process according to any one of claims 6 to 10, wherein the emulsion or the suspension is agitated at a temperature comprised between l99CP1033i.SPB.23 -24- 400 and 750C.

12. Cosmetic or pharmaceutical compositions according to claim 1, substantially as herein described with reference to any one of the Examples.

13. Preparation process according to claim 6 which process is substantially as herein described with reference to any one of the Examples

14. A method for the treatment of adenomas and neoplasias of the prostate, for combatting benign hypertrophy of the prostate, for the treatment of benign or malignant tumours the cells of which contain in particular androgen receptors in a patient requiring said treatment which method comprises administering to said patient an effective amount of a cosmetic or pharmaceutical composition according to any one of claims 1 to A method for the treatment of hirsutism, acne, serborrhea, androgenic alopecia or hyperpilosity in a patient requiring said treatment which method comprises administering to said patient an effective amount of a cosmetic or pharmaceutical composition according to any one of claims 1 to

16. Use of a cosmetic or pharmaceutical composition according to any one of claims 1 to 5, for the preparation of a medicament for treatment of adenomas and neoplasias of the prostate, for combatting benign hypertrophy of the prostate, or for the treatment of benign or malignant tumours the cells of S which contain particular androgen receptors.

17. Use of a cosmetic or pharmaceutical composition according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of hirsutism, acne, serborrhea, androgenic alopecia or hyperpilosity. DATED this 21st day of April, 1999. i265 HOECHST MARION ROUSSEL LTD 00:0 By their Patent Attorneys: CALLINAN LAWRIE 21/4/99CF10335.SPE,24