EP2124960A1

EP2124960A1 - 3-hydroxychlormadinone acetate for the topical treatment of androgen-dependent skin diseases

Info

Publication number: EP2124960A1
Application number: EP07856867A
Authority: EP
Inventors: Georg Schramm; Christa Kneip
Original assignee: Gruenenthal GmbH
Current assignee: Richter Gedeon Nyrt
Priority date: 2006-12-22
Filing date: 2007-12-19
Publication date: 2009-12-02
Also published as: DE102006062120A1; WO2008077542A1; US8465763B2; US20090318395A1

Abstract

The invention relates to the use of 3ß-hydroxychlormadinone acetate (17a-acetoxy-chloropregna-4,6-dien-3ß-ol-20-one) and/or 3a-hydroxychlormadinone acetate (17a-acetoxy-chloropregna-4,6-dien-3a-ol-20-one) for the production fo a medicament for the treatment of the skin, preferably human skin by means of topical application and a pharmaceutical or cosmetic composition containing 3ß-hydroxychlormadinone acetate and/or 3a-hydroxychlormadinone acetate.

Description

3-HYDROXY-CHLOROMADINONE ACBATE FOR THE TOPIC TREATMENT OF ANDROGEN-DEPENDENT

HAUTERKRANKUNGΞN

The present invention relates to the use of 3β-hydroxy-chlormadinone acetate (17α-acetoxy-chloropregna-4,6-diene-3β-ol-20-one) and / or 3α-hydroxy-chloro-madinone acetate (17α-acetoxy) chloropregna-4,6-diene-3α-ol-20-one) for the manufacture of a medicament for the treatment of skin, preferably human skin by topical application, as well as a pharmaceutical or cosmetic composition containing 3β-hydroxy-chlormadinone acetate and / or 3α-hydroxy -chlormadinonacetat.

In Central Europe, the number of hormonal skin diseases such as acne, alopecia, seborrhea and / or hirsutism is estimated at 35% and 50%, respectively. Acne, alopecia, seborrhea and hirsutism are mostly androgen-dependent diseases.

Acne, especially "common" acne, is mainly caused by increased androgen during puberty, and is caused by a genetic over-sensitivity to the hormone dihydrotestosterone (DHT), an androgenic hormone Sebaceous glands and in hirsutism, excessive hair growth occurs according to the male pattern of distribution in women.

By hormonal treatment, in particular by progestins with antiandrogenic effect, the disease course of these androgen-dependent diseases can be favorably influenced. Such antiandrogenic gestagens are usually administered orally.

In WO 86/01402, WO 91/06284 and EP 0 765 663, the progestins chlormadinone acetate (CMA), cyproterone acetate (CPA) and megestrol acetate (MGA) are used for the production of Position of a drug for topical application of androgen-dependent diseases described.

A disadvantage of these topically applied, antiandrogenic drugs, however, is that their topical application also leads simultaneously to a high systemic exposure to the respective active ingredient.

The object of the present invention was therefore to provide a pharmaceutical or cosmetic composition for the topical treatment and / or prophylaxis of androgen-dependent diseases, in the use of which the systemic exposure to the corresponding active ingredient is practically negligible. Therefore, these compositions are said to be suitable for topical treatment of the skin and hair of both female and male patients.

This object is achieved by the use of 3β-hydroxy-chlormadinone acetate (17α-acetoxy-chloropregna-4,6-diene-3β-ol-20-one) and / or 3α-hydroxy-chloro-dinatoacetate (17α-acetoxy-chloroprene). 4,6-diene-3α-ol-20-one) for the manufacture of a medicament for the topical treatment of skin, preferably human skin, and possibly also hair.

The antiandrogenic active ingredients 3β-hydroxy-chlormadinone acetate and 3α-hydroxy-chlormadinone acetate are surprisingly characterized by a far lower skin penetration compared to CMA, whereby a systemic active ingredient loading is practically prevented by an effective treatment of androgen-dependent diseases by topical application.

A further subject of the present invention is also a pharmaceutical composition for treating the skin by topical application comprising 3β-hydroxy-chlormadinone acetate and / or 3α-hydroxy-chlormadinone acetate in an amount of 0.01 to 20% by weight, preferably 0.01 to 10% by weight, based on the total weight of the pharmaceutical composition according to the invention, and at least one pharmaceutically acceptable vehicle, preferably in conventional amounts. The term "pharmaceutically acceptable vehicle" within the meaning of the invention means conventional pharmaceutical auxiliaries and additives for the formulation of pharmaceutical compositions, such as pharmaceutically acceptable buffers, preservatives, reducing agents, antioxidants, UV absorbers, stabilizers, penetration promoters, emulsifiers, gelling agents, thickeners, surfactants , Fragrances, flavor additives and dyes. Such auxiliaries and additives are generally preferably pharmaceutically acceptable.

Suitable buffers which can be used for the pharmaceutical composition according to the invention are known to the person skilled in the art. For example, succinic acid, citric acid, lactic acid, phosphoric acid, trisodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate and combinations of lactic acid and sodium hydroxide can be used as buffers. Preferably, the pH of the composition is adjusted to 5.5-7.5 with the buffer.

Antioxidants, reducing agents and / or UV absorbers can be used as stabilizers or preservatives. Particularly preferred for the pharmaceutical composition according to the invention, at least one reducing agent selected from the group comprising sulfites, such as sodium sulfite, potassium sulfite, ammonium sulfite, sodium hydrogen sulfite, potassium bisulfite, sodium bisulfite, calcium sulfite, calcium bisulfite, potassium bisulfite, sodium disulfite, ammonium bisulfite, sodium metabisulfite, potassium metabisulfite; Mercaptocarboxylic acids such as 2-mercaptopropionic acid, 3-mercaptopropionic acid, mercapto-succinic acid, thioglycolic acid, ammonium thioglycolate, sodium thioglycolate, L-cysteine, dimercapto-adipic acid; Mercapto-amines such as L-cysteine ethyl ester, L-cysteine methyl ester, N-acetyl-L-cysteine, cysteamine; Mercaptoamides, such as thioglycolamide, N-hydroxyethyl mercaptoacetamide, N-methylmercaptoacetamide, 2-mercapto-propionamide; Hydroxides, such as guanidine hydroxide, sodium hydroxide; Alcohols and diols such as resorcinol, thioglycerol, glycerol monothioglycolate, glycol thioglycolate; Di-thio compounds, such as dihydrolipoic acid, sodium dihydrolipoic acid, dithiothreitol, 1,3-dithiopropanol; Lithium chloride, tris (hydroxymethyl) phosphine, thioglycol hydrazide, 2-mercaptoethanesulfonic acid, homocysteine thiolactone, polythiol polymers, salts of hydrogen sulfide, amines in alkaline solution, salts of hydrogen cyanide, borohydride, dithionite, ester salts of sulphoxylates, formic acid, oxalic acid, diazolidinyl urea, iodopropynylbutyl carbamate, chloromethylisotiazolinone, methylisothiazolinone, butylparaben, ethylparaben, methylparaben, propylparaben, isobutylparaben and phenoxyethanol used. The stabilizers are preferably used in an amount of 0.001 to 2% by weight, based on the total weight of the pharmaceutical composition according to the invention.

Preferably, as antioxidant component for the pharmaceutical composition according to the invention, at least one antioxidant is selected from the group comprising ascorbic acid (vitamin C), sodium L-ascorbate, calcium L-ascorbate, ascorbyl palmitate, butylhydroxyanisole, butylhydroxytoluene, calcium diisodium EDTA, propyl gallate, octyl gallate, dodecyl gallate (lauryl gallate), isoascorbic acid, sodium isoascorbate, lecithin, lactic acid, polyphosphate, sulfur dioxide, selenium, tocopherol (vitamin E), α-tocopherol, γ-tocopherol, δ-tocopherol, stannous chloride , Citric acid, sodium citrate and potassium citrate. The antioxidant is preferably used in an amount of 0.001 to 2 wt .-%, based on the total weight of the pharmaceutical composition according to the invention.

For the pharmaceutical composition according to the invention, the following compounds may preferably be used as UV absorbers:

(A) p-aminobenzoic acid (PABA) type UV absorber, such as p-aminobenzoic acid,

PABA monoglycerol ester, NN-dipropoxy-PABA-ethyl ester, N, N-diethoxy-PABA-ethyl ester, N, N-dimethyl-PABA-ethyl ester, N, N-dimethyl-PABA-butyl-ester, N, N-dimethyl-PABA-amyl ester and N, N-dimethyl PABA octlyl ester.

(B) Anthranilic acid type UV absorbers, such as homomethyl-N-acetyl-anthranilic acid.

(C) Salicylic acid type UV absorber: amyl-salicylic acid, menthyl-salicylic acid, homo-salicylic acid, octyl-salicylic acid, phenyl-salicylic acid, benzyl-salicylic acid and / or p-isopropanol-phenyl-salicylic acid.

(D) cinnamic acid type UV absorbers such as octyl cinnamic acid, ethyl 4-isopropyl cinnamic acid,

Methyl 2,5-diisopropyl cinnamic acid, ethyl 2,4-diisopropyl cinnamic acid, methyl 2,4-diisopropyl cinnamic acid, propyl p-methoxycinnamic acid, isopropyl p-methoxy cinnamic acid acid, isoamyl-p-methoxycinnamic acid, octyl-p-methoxy-cinnamic acid (or 2-ethylhexyl-p-methoxycinnamic acid), 2-ethoxyethyl-p-methoxycinnamic acid, cyclohexyl-p-methoxycinnamic acid, Ethyl α-cyano-β-phenyl-cinnamic acid, 2-ethylhexyl-α-cyano-β-phenyl-cinnamic acid and / or glycerol mono-2-ethylhexanoyl-diparamethoxycinnamic acid.

(E) Benzophenone-type UV absorbers, such as 2,4-dihydroxybenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone non, 2,2 ', 4,4'-tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4'-methylbenzophenone, 2-hydroxy-4-methoxy benzophenone -5-sulfonic acid salts, 4-phenylbenzophenone, 2-ethylhexyl-4'-phenylbenzophenone-2-carboxylate, 2-hydroxy-4-n-octoxybenzophenone and / or 4-hydroxy-3-carboxy- benzophenone.

(F) Other UV absorbers, such as 3- (4'-methylbenzylidene) -D, L-camphor, 3-benzylidene-

DL camphor, urocanic acid, ethylurocanoic acid, 2-phenyl-5-methylbenzoxazole, 2,2'-hydroxy-5-methylphenylbenzotriazole, 2- (2'-hydroxy-5'-t-octylphenyl) benzotriazole, 2- (2 ¹ -hydroxy-5'-methylphenyl) benzotriazoles, dibenzalazine, dianisoylmethane, 4-methoxy-4 ¹ -t-butyl-dibenzoylmethane, 5- (3,3-dimethyl-2-norbornylidene) -3-pentane 2-one, calcium, barium, alumina, iron oxide and / or titanium dioxide.

The UV absorber is preferably used in an amount of 1 to 10 wt .-%, based on the total weight of the pharmaceutical composition according to the invention.

The pharmaceutical composition of the invention may optionally contain other pharmaceutically acceptable additives such as, for example, penetration promoters, solvents such as water and / or alcohols, surfactants, gelling agents, plasticizers, emulsifiers, stabilizers, hydrophobic or hydrophilic polymers, fragrances, film formers and / or thickeners unless such additives affect skin penetration.

Suitable penetration promoters for the purposes of the present invention preferably comprise penetration promoters selected from the group comprising acid amides and amines. Particularly preferred is as a penetration promoter Urea used. The penetration promoter is preferably used in an amount of 0.5 to 10 wt .-%, based on the total weight of the pharmaceutical composition according to the invention.

Emollients can be used in the preparation of the pharmaceutical composition according to the invention in amounts such that dehydration of the skin is prevented or reduced. As emollients, preferably at least one compound selected from the group comprising oils, waxes, silicone oils, triglyceride esters, acetoglyceride esters, ethoxylated glycerides, alkyl esters, alkenyl esters, fatty acids, fatty alcohols, fatty alcohol esters, lanolin, lanolin derivatives, polyhydric alcohols, their ethers, polyhydrogenated Alcohol esters, wax esters, beeswax derivatives, vegetable waxes, phospholipids, sterols and amides. The emollients are preferably used in an amount of from 1 to 25% by weight, based on the total weight of the composition according to the invention.

Preferred emulsion stabilizers in the composition according to the invention include nonionic, anionic, cationic and amphiphilic surfactants which are preferably selected from the group comprising polyethylene glycol, polyethylene glycol derivatives, tweens, tritons, spans, polyglycerols, polyalkyl glycerides, alkyl sulfonates, aryl sulfonates, alkyl phosphates, aryl phosphates, alkyl Betaine derivatives and phosphatidylglycerol. The emulsion stabilizers are preferably used in an amount of 0.1 to 5 wt .-%, based on the total weight of the composition according to the invention.

Emulsifiers are preferably added to the composition in such amounts as to allow for uniform mixing of the components of the pharmaceutical composition of the invention. Conventional emulsifiers are preferably anionic, cationic and / or nonionic emulsifiers. Examples of such emulsifiers include preferably potassium stearate, sodium stearate, ammonium stearate, triethanolamine stearate, glycerol monostearate, sodium lauryl-5-sulfate, sodium acetyl sulfate, N- (stearoyl-colamino-formylmethyl) -pyridine-chloride, N-soy-N-ethyl-morpholine ethosulfate, alkyl- dimethylbenzyl ammonium chloride, diisobutylphenoxythioxyethyldimethylbenzyl ammonium chloride, acetylpyridium chloride, monostearate, polyethylene oxide stearate, polyethylene oxide sorbitan monostearate, sorbitan, propylene glycol monostearate and / or ethoxylated lanolin. The emulsifier component is preferably used in an amount of from 0.1 to 10% by weight, based on the total weight of the pharmaceutical composition according to the invention.

Furthermore, it is also possible to use surfactants (surfactants) which have nonionic, cationic, anionic and / or ampholytic properties.

Nonionic surfactants are preferably used for the production of the pharmaceutical composition according to the invention, such as preferably sorbitan esters, such as sorbitan monolaurate, sorbitan monooleate, sorbitan monoisostearate; Polyethylene oxide sorbitan esters, such as polyethylene oxide sorbitan monoisostearate, polyethylene oxide sorbitan monolaurate, polyethylene oxide sorbitan monooleate; Glycerol esters, such as glycerol monoisostearate, glycerol monomyristate; Polyethylene oxide glycerol ethers such as polyethylene oxide glycerol monoisostearate, polyethylene oxide glycerin monomyristate; Polyglycerol fatty acid esters, such as diglycerol monostearate, decaglycerol decaisostearate, diglycerol diisostearate; Glycerol fatty acid esters, such as glycerol monocaprate, glycerol monolaurate, glycerol monomyristate, glycerol monopalmitate, glycerol monooleate, glycerol monostearate, glycerol monolinoleate, glycerol monoisostearate, glycerol monodilinoleate, glycerol monodicaprate; Polyethylene oxide glycerin fatty acid esters, such as polyethylene oxide glycerol monomyristate, polyethylene oxide glycerol monooleate, polyethylene oxide glycerol monostearate; Polyethylene oxide branched alkyl ethers such as polyethylene oxide-octyldodecyl alcohol, polyethylene oxide-2-decyl tetradecyl alcohol; Polyethylene oxide alkyl ethers such as polyethylene oxide oleyl alcohol ethers, polyethylene oxide acetyl alcohol ethers; Polyethylene oxide-hydrogenated castor oil fatty acid esters such as polyethylene oxide-hydrogenated castor oil, polyethylene oxide dihydrocholesterol ethers, polyethylene oxide hydrogenated castor oil isostearate and / or polyethylene oxide alkylaryl ethers such as polyethylene oxide octyl phenol ethers.

Used anionic surfactants for the pharmaceutical composition according to the invention preferably comprise salts, such as diethanolamine salt, Triethanolamine salt, amino acid salt, sodium salt, potassium salt; higher fatty acids, such as oleic acid, stearic acid, isostearic acid, palmitic acid, myristic acid, ether carboxylic acid-alkaline salts, N-acylamino acid salts and higher alkylsulfonic acid salts. The surfactant is preferably used in an amount of 0.1 to 10% by weight, based on the total weight of the pharmaceutical composition according to the invention.

Gel formers suitable for the compositions of the invention preferably comprise natural or synthetic polymers. Natural polymers are preferably selected from the group comprising agar-agar, alginic acid, alginate, amidated pectin, propylene glycol alginate, carbomer, carrageenan, casein, dammar gum, dextrins, furcellaran, gelatin, guar gum, guar gum, gellan, ghatti gum, gum arabic Gum made from spruce juice, locust bean gum, karaya gum, keratin, konjac flour, L-HPC, locust bean gum, mastic, pectin, shellac, starch (if necessary modified), tara gum, tragacanth, xanthan gum and their derivatives. Preferred synthetic polymers which can be used as gelling agents for the composition according to the invention are selected from the group comprising acrylic acid polymers, carbomers, polyacrylamides and alkylene oxide polymers. The gelling agents are preferably used in an amount of from 0.1 to 5% by weight, based on the total weight of the composition according to the invention.

Thickening agents which may preferably be included in the compositions of the present invention include, for example, candelilla, carnauba and microcrystalline waxes, carbomer and polyethylene oxide thickeners. The thickening agent is preferably used in an amount of 0.5 to 2 wt .-%, based on the total weight of the pharmaceutical composition according to the invention.

The pharmaceutical composition of the invention may preferably contain at least one dye and / or fragrance.

In a preferred embodiment of the pharmaceutical composition according to the invention, there is at least one compound as perfume or flavor additive selected from the group comprising unsaturated or saturated, acyclic, monocyclic or bicyclic monoterpenes and sesquiterpenes before, each with 1, 2, 3 or 4 identical or different substituents selected from the group comprising a -OH, oxo (= 0 or -O -), -OC _1-5 -alkyl, -O-phenyl, -C (= O) -OH, -C (= O) -OC _1-5 -alkyl, -C (= O) -O-phenyl, -OC (= O) -C _1-5 alkyl, -OC (= O) -phenyl group and -CN may be substituted, wherein the alkyl and / or phenyl radical having 1, 2 or 3 substituents selected from the group comprising OH, oxo (= 0) and -OC-ι- ₅ alkyl may be substituted;

Phenyl or naphthyl compounds, each containing 1, 2, 3, 4 or 5 identical or different substituents selected from the group comprising a -C (= O) -H, -C (= O) -C _1-5 - alkyl, -C (= O) -phenyl, -OH, -C _1-5 alkyl, -C _{_2-5} alkenyl, -OC _1-5 alkyl, -O- C (= O) -C _-5 -Alkyl, -OC (= O) -C _2-6 -alkylene, -OC (= O) -phenyl, -OC (= O) -OH, phenyl, -C (= O) -OH, -C (= O) -OC _1-5 -alkyl, -C (= O) -OC _2-8 -alkenyl, -C (= O) -O-phenyl, -C (= O) -O-C _3-8 -cycloalkyl , -CH = C (. ₁ C ₅ alkyl) (C (= O) -H) _l -NO ₂ and -NH ₂ group may be substituted, wherein the substituents in each case via a linear or branched Ci _-7 - alkylene - or C _2-5 alkenylene bridge may be bonded, each of which may be substituted by 1, 2 or 3 identical or different substituents selected from the group comprising F, Cl and Br;

Phenyl or naphthyl compounds which may be condensed with 1 or 2 unsaturated or saturated 5- to 7-membered aliphatic rings, wherein the rings are each 1, 2 or 3 heteroatom (s) selected from the group consisting of oxygen, nitrogen and May have sulfur as a ring member (s) and be substituted with 1, 2, 3, 4 or 5 identical or different substituents selected from the group comprising a Ci _-5- alkyl, -OH and -O-Ci _-5- alkyl group can;

and

unsaturated or saturated, unsubstituted, linear, branched or cyclic esters, alcohols and aldehydes containing from 5 to 20, preferably from 5 to 16, carbon atoms and optionally 1, 2 or 3 heteroatom (s) selected from the group consisting of oxygen and sulfur Chain or ring member (s) he have, before. The pharmaceutical composition according to the invention as fragrance or flavor additive particularly preferably comprises at least one natural or nature-identical compound selected from the group comprising anethole, benzaldehyde, benzyl acetate, benzyl alcohol, benzyl formate, isoboron acetate, camphor, neral, citronellal, citronellol, citronellyl acetate, para- Cymene, decanal, dihydrolinalool, dihydromyrcenol, dimethylphenylcarbinol, eucalyptol, geraniol, geranylacetate, geranylnitrile, cis-3-hexenylacetate, hydroxycitronellal, limonene, linalool, linalooloxide, linalylacetate, linalylpropionate, methylanthranilate, alpha-methylionone, methyl nonylacetaldehyde , Methylphenylcarbinylacetate, menthone, iso-menthone, myrcene, myrcenylacetate, myrcenol, nerol, nerylacetate, nonylacetate, phenylethylalcohol, alpha-pinene, beta-pinene, gamma-terpinene, alpha-terpinol, beta-terpinol, terpinylacetate, para-tert Butylcyclohexyl acetate, alpha-amyl cinnamic aldehyde, amyl salicylate, caryophyllene, cedrene, cinnamyl alcohol, D imethylbenzylcarbinylacetate, ethylvanillin, eugenol, iso-eugenol, tricyclodecenylacetate, piperonal, 3-cis-hexenylsalicylate, hexylsalicylate, lilial, gamma-methylionone, nerolidol, patchouli alcohol, phenylhexanol, beta-selinen, trichloromethylphenylcarbinylacetate, triethylcitrate, vanillin, dimethoxybenzaldehyde, benzophenone, Ethylenebasylate, galaxolide, hexylcinnamaldehyde, lyral, methylcedrylon, methyl-beta-naphthylketone, muskketone, phenylethylphenylacetate, ambrettolide, cyclohexylsalicylate, delta-nonalactone, delta-undecalactone, dodecalactone, ethylenecodylenate, exaltolide, gamma undecalactone, hexadecanolide, myristicin and musk xylene.

Other fragrances or flavor additives which may comprise the pharmaceutical composition of the invention are disclosed in David J. Rowe, Chemistry and Technology of Flavors and Fragrances, Taylor & Francis Group, 2004; Michael Edwards, Fragrances of the World 2005, Crescent House Pub, 2004 and David Pybus, The Chemistry of Fragrances, Royal Society of Chemistry, 1999. The relevant disclosures are hereby incorporated as part of the present disclosure.

As a fragrance for the pharmaceutical composition according to the invention, at least one naturally occurring mixture of fragrances or aroma additives can also be used. In particular, at least one Duftstoffbzw. Aromatic addition mixture selected from the group comprising rosemary oil, sandalwood oil, violet oil, lemongrass oil, lavender flower oil, eucalyptus oil, pepper Mint oil, Chamomile oil, Clove leaf oil, Cinnamon oil, Thyme oil, Tea tree oil, Cajeput oil, Niaolin oil, Manuka oil, Citrus oil, Mountain pine oil, Jasmine oil, Geranium oil, Cumin oil, Spruce needle oil, Bergamot oil, Turpentine oil, Linalol oil, Blood orange oil, Cypress oil, Edible tan oil, Fennel oil, Grapefruit oil, ginger oil, pine oil, lavandin oil, lemongrass oil, lime oil, tangerine oil, lemon balm oil, myrrh oil, patchouli oil, rosewood oil and thuja oil.

The perfume or flavor additive is preferably used in an amount of 0.001 to 2 wt .-%, based on the total weight of the pharmaceutical composition according to the invention.

Preferred dyes for the pharmaceutical composition according to the invention include:

A) inorganic and organic pigments, such as titanium dioxide,

Zirconia, ceria, zinc oxide, iron oxide, Prussian blue, carbon black, calcium lake and aluminum lake.

B) fat-soluble dyes, such as Sudan red, DC Red 17, DC Green 6,

Beta Caroten, Soybean Oil, Sudan Brown, DC Yellow 11, DC Violet 2, DC Orange 5 and Quinoline Yellow.

C) water-soluble dyes, such as iron sulfates, (Rhodamine), methylene blue and natural dyes.

The dye is preferably used in an amount of 0.001 to 2 wt .-%, based on the total weight of the pharmaceutical composition according to the invention.

The pharmaceutical composition according to the invention is preferably characterized in that the active ingredient (s) 3β-hydroxy-chlormadinone acetate and / or 3α-hydroxy-chlormadinone acetate is preferably present in a molecularly dispersed form in a hydrophilic component.

The hydrophilic component used is preferably sugar or sugar-like substances, such as sucrose, lactose, mannitol, sugar alcohol, urea or other nitrogen-containing compounds. Alternatively, the pharmaceutical composition according to the invention may preferably contain the active ingredient 3β-hydroxy-chlormadinone acetate and / or 3α-hydroxy-chlormadinone acetate in a moisturizing base, optionally in a molecularly dispersed manner in combination with a hydrophilic component.

Such a preparation based on a moisturizing base additionally counteracts the stimulation for the overproduction of fat through the skin, by controlling a certain amount of fat necessary for the reconstitution of the skin. Typical refatting preparations are known in the art and include, for example, lipogels or oil-in-water emulsions.

The pharmaceutical composition according to the invention can be used as liquid, foam, cream, gel, paste, balm, spray, ointment, lotion, conditioner, tonic, tincture, milk, mus, powder for dissolving, emulsion (oil-in-oil). Water, water-in-oil), serum, oil, shampoo, suspension such as liposomes or nanosomes, or formulated as a dispersion.

The preparation of corresponding formulations containing the pharmaceutical composition according to the invention and the auxiliaries and additives which are usually used are known to the person skilled in the art. For this purpose, e.g. on Bauer et al., "Textbook of Pharmaceutical Technology" 6th edition, WVG Stuttgart, 1999, the pertinent disclosures of which are hereby incorporated by reference as disclosure of the present application.

The pharmaceutical composition according to the invention is particularly preferably characterized in that it contains as vehicle at least one buffer, at least one preservative, at least one flavor additive and / or at least one excipient and preferably as cream, ointment, lotion, gel, tincture, coatable mask, spreadable mass, tonic, hair balm, hair conditioner, hair gel, hair conditioner, hair tonic, hair cream or hair shampoo is formulated.

Another object of the present invention relates to a cosmetic composition for the care of the skin and possibly also the hair by topical see or external application comprising 0.01 to 5 wt .-%, preferably 0.01 to 2 wt .-%, of Sß-hydroxy-chlormadinone acetate and / or 3α-hydroxy-chlormadinonacetat and at least one cosmetic vehicle, preferably in conventional Quantities, wherein the percentage proportion of 3ß-hydroxy-chlormadinone acetate and / or 3α-hydroxy-chlormadinone acetate in each case based on the total weight of the cosmetic composition according to the invention.

As cosmetic vehicles, the customary auxiliaries and / or additives for cosmetic compositions are preferably suitable. Preferably, the excipients and additives listed above may be used, which are used for the formulation of pharmaceutical compositions. These additives or adjuvants are also preferably physiologically acceptable. The amounts of the respective components are preferably chosen so that the cosmetic composition according to the invention is in conformity with EU Cosmetics Directive 76/768 / EEC or EU Directive 95/17 / EC.

As already stated, it has surprisingly been found that the antiandrogenic active ingredients 3β-hydroxy-chlormadinone acetate and 3α-hydroxy-chlormadinone acetate are characterized by a 6-fold lower skin penetration and a 0.7-fold higher antiandrogenic activity compared to CMA. Due to these advantageous properties, systemic drug exposure is virtually prevented in topical treatment of androgen-dependent diseases.

Another object of the present invention is therefore the use of 3ß-hydroxy-chlormadinonacetat and / or 3α-hydroxy-chlormadinoneacetat for the manufacture of a medicament for the topical treatment of skin, preferably human skin and optionally the hair, preferably for topical local treatment of androgen dependent diseases, most preferably for the prophylaxis and / or treatment of androgen-dependent diseases such as acne, alopecia, seborrhea and / or hirsutism.

Acne is mainly a disease of the sebaceous follicle, which initially produces noninflammatory comedones, but later also a Series of inflammatory efflorescences (including papules, pustules, and nodules). Some types of acne can affect terminal and vellus hair follicles.

Acne is systematized by cause, severity or severity and age.

Acne can also be caused exogenously ("from the outside").

Acne inversa is a frequently severe inflammation of the sebaceous glands and terminal hair follicles, preferably in intertriginous areas such as e.g. Armpit, inguinal region and gluteal fold.

By severity or severity acne comedonica is distinguished from acne papulopustulosa and acne conglobata. The complexion of acne comedonica is characterized by comedones and at most a few, very slight inflammations (papules). Scarring is not to be feared. In acne papulopustulosa papules and pustules dominate, scarring as a result of inflammatory processes is possible. The acne conglobata denotes the additional occurrence of fistula comedones and nodules, as a result threatens significant scarring. Acne can occur both in acute and in chronic form.

Alopecia / alopecia generally refers to a visible clearing of the scalp hair, i. a condition with abnormally "thinning" hair or hairless skin in the sense of a bald head.

The most common form of alopecia includes androgenetic hair loss (alopecia androgenetica).

Seborrhoea is a medical term for the pathologically altered secretion of sebaceous glands. It is associated with deficiency of biotin (vitamin B7) as well as vitamin B6 (pyridoxine). The term is sometimes also used for seborrheic dermatitis. Patients with seborrhea often also suffer from too dry skin and keratinization. Seborrhea oleosa causes an oily texture of the skin, seborrhoe sicca manifests in glandular, fatty scales. The Seborr Höe promotes, inter alia, the occurrence of rosacea, acne vulgaris and acne necroticans.

According to the International Statistical Classification of Diseases (ICD) of the World Health Organization (WHO), Seborrhoea is assigned to the categories "Seborrheic Dermatitis (Seborrheic Dermatitis)" L21 and "Seborrheic Keratosis" L82, with the class L21 continuing in subclasses L21.0 (Seborrhoea capitis, seborrheic cradle cap), L21.1 (Seborrheic dermatitis of children), L21.8 (Other seborrheic dermatitis), L21.9 (Seborrheic dermatitis, unspecified) and L82 class Dermatosis papulosa nigra and the reader Tre / af syndrome.

Hirsutism (ICD class L68.0) is excessive male-pattern hair growth in women, which can be triggered either by the increased formation of male sex hormones (testosterone) or by psychogenic factors such as social stress or anxiety syndrome.

Particularly preferred is the use of 3β-hydroxy-chlormadinone acetate and / or 3α-hydroxy-chlormadinone acetate for the manufacture of a medicament for the prophylaxis and / or treatment of seborrhea, acne, alopecia, and / or hirsutism, such prophylaxis and / or treatment being preferred a topical topical treatment of the skin and / or hair and / or to promote hair growth in both female and male patients. Particularly preferred is the preferably topical local application of the medicament for the treatment of seborrhea, acne vulgaris, androgenetic alopecia, and / or hirsutism.

The medicament according to the invention contains preferably 0.01 to 20, more preferably 0.01 to 10 and very particularly preferably 0.01 to 5 wt .-% of 3ß-hydroxy chlormadinonacetat and / or 3α-hydroxy-chlormadinonacetat, based in each case on the total weight of the medicament according to the invention. Another object of the present invention is the use of a - as described above - cosmetic care of the skin and optionally the hair by topical application, preferably of humans, preferably for the prevention and / or use in seborrhea and / or acne, preferably Acne vulgaris, androgenetic alopecia and / or to promote hair growth in both female and male patients.

For topical treatment, the pharmaceutical or cosmetic composition according to the invention is preferably applied to the human skin and / or to the hair at least once a day, more preferably 3 times a day and most preferably 2 times a day.

Preferably, the pharmaceutical or cosmetic composition of the invention is applied to the scalp, facial skin, the skin of the upper body, such as the skin of the back and / or the chest and / or on the hair.

The following examples serve to illustrate the invention in more detail, but are not to be construed as limiting their scope:

Example 1: A pharmaceutically active solution of:

3β-hydroxy-chloroadinone acetate 2.0 g

Isopropyl myristate 10 g

EDTA (ethylenediaminetetraacetic acid) 0.025 g

Ethanol 96% 35.0 g

Transcutol (diethylene glycol monoethyl ether) 2.0 g

Propylene glycol 50.975 g

is made by mixing and dissolving the components.

Example 2: A cosmetic solution of:

3β-Hydroxy-chloroforminone acetate 1, 0 g Carbomer 940 1, 0 g

Propylene glycol 10.0 g

Na-EDTA 0.025 g

Methyl parabens 0.12 g

Propylparabene 0.05 g

Urea 2.0 g

Purified water 75.8 g

is prepared by mixing and dissolving the components and then adjusting the pH to 5.5 using a 10% NaOH solution.

Example 3: Determination of permeation of chlormadinone acetate (CMA) and 3β-hydroxy-chlormadinone acetate by human abdominal skin

Human abdominal skin pieces incurred in abdominal reduction operations were placed in a Petri dish containing dissecting solution (Na ⁺ : 144 mmol / L, K ⁺ : 5.9 mmol / L, Ca ²⁺ : 3.7 mmol / L, Cl ^" : 157 mmol / L) The pieces of skin were removed from the corium side, while moisturizing with the preparation solution, in several steps up to a layer thickness of about 300 μm, resulting in a mechanically stable skin preparation consisting of epidermis with about 150-200 μm cutis Layer thickness of the skin preparations was determined by measuring with a micrometer MITUTOYO The surface of the skin preparations used was about 19.7 mm ² .

The determination of the permeation of CMA and 3β-hydroxy-chlormadinone acetate by human abdominal skin was carried out in a flow cell, which is shown schematically in FIG. Here, a receptor fluid (1) was pumped past the underside of the skin preparation (2) with a peristaltic pump at a rate of 270 μl per hour. The skin preparation was clamped between the upper part (3) and the lower part (4) of the permeability cell (5). From above, in each case vehicle with 3β-hydroxy-chlormadinone acetate (5% suspension in aqueous 0.05% polysorbate 80 solution) or chlormadinone acetate (5% suspension in aqueous 0.05% polysorbate 80 solution) the skin is applied, the closing by the skin preparation (2) diffused into the receptor fluid (1). The skin preparation was moistened by a stationary donor fluid (9) located in a reservoir (7). The internal diameter of the receptor liquid supply line (6) was 0.6 mm, and the receptor fluid volume under the skin was about 80 μl. The receptor fluid (1) was collected at fixed time intervals using a fraction collector (8) and subsequently analyzed by HPLC. These experiments gave a quantitative statement about the amount of substance diffused as a function of time.

As the receptor liquid, an aqueous, isotonic Tris buffer (20 mmol / l) was used with 20% ethanol and adjusted with NaCl to 310 mosmol (0.9 wt.%). The pH of the receptor fluid was 7.35. From a plaster containing the drug to be examined, a piece of the surface of the skin preparation corresponding piece was punched out by means of a punch and adhered to the skin preparation. The test duration was 21 h and the sample interval was 3 h. The experiments were carried out at a test temperature of 34 ° C. In each case 3 independent series of measurements with CMA and 3β-hydroxy-chloroforminone acetate were made.

The mean delivered dose (mean of 3 independently performed experiments) by human abdominal skin at 24 hours was 4.4 μg for CMA and 0.7 μg for the metabolite 3β-hydroxy-chlormadinone acetate, respectively. The skin permeability of 3β-hydroxy-chlormadinone acetate is thus much lower than that of CMA.

LIST OF REFERENCE NUMBERS

1 receptor fluid (mobile phase)

2 skin preparation

3 Upper part of the permeability cell

4 lower part of the permeability cell

5 permeability cell

6 receptor fluid supply line

7 reservoir for donor fluid

8 fraction collectors

9 donor liquid (stationary phase)

Claims

claims

1. Use of S-hydroxy-chlormadinone acetate (17α-acetoxy-chloropregna-4,6-diene-3β-ol-20-one) and / or Sα-hydroxy-chlormadinone acetate (17α-acetoxy-chloropregna-4,6-diene 3α-ol-20-one) for the manufacture of a medicament for the topical treatment of skin, preferably human skin and optionally hair.

2. Use according to claim 1 for the preparation of a medicament containing 0.01 to 20 wt .-% of 3ß-hydroxy-chlormadinonacetat and / or 3α-hydroxy-chloromonadinacetat.

3. Use according to claim 1 or 2 for the topical treatment of androgen-dependent diseases.

4. Use according to one of claims 1 to 3 for the prophylaxis and / or treatment of seborrhea, acne, preferably acne vulgaris, hirsutism and / or alopecia, preferably androgenetic alopecia and / or for the promotion of hair growth in both female and male patients.

A pharmaceutical composition for the treatment of the skin by topical application comprising 0.01 to 20% by weight of 3β-hydroxy-chlormadinone acetate and / or 3α-hydroxy-chlormadinone acetate and at least one pharmaceutically acceptable vehicle.

6. Cosmetic composition for the care of the skin by topical application comprising 0.01 to 5 wt .-% of 3ß-hydroxy-chlormadinonacetat and / or 3α-hydroxy-chlormadinonacetat and at least one cosmetic vehicle.

7. A pharmaceutical or cosmetic composition according to claim 5 or 6, characterized in that it contains as a vehicle at least one buffer, at least one preservative, at least one flavor additive and / or at least one excipient.

8. Pharmaceutical or cosmetic composition according to one of claims 5 to 7, characterized in that the pharmaceutical or cosmetic composition as cream, ointment, lotion, gel, tincture, coatable mask, spreadable mass, tonic, hair balm, hair conditioner, hair gel, hair conditioner, Hair tonic, hair cream or hair shampoo is formulated.

9. Pharmaceutical or cosmetic composition according to claim 7 or 8, characterized in that the preservative is at least one compound selected from the group comprising antioxidants, reducing agents and UV absorbers.

10. A pharmaceutical or cosmetic composition according to any one of claims 7 to 9, characterized in that the / the active ingredient (s) 3ß-hydroxy-chlormadinone acetate and / or 3α-hydroxy-chlormadinonacetat present in a hydrophilic component molecularly dispersed (s).

11. A pharmaceutical or cosmetic composition according to any one of claims 7 to 10, characterized in that therein the active ingredient 3ß-hydroxy-chlormadinone acetate and / or 3α-hydroxy-chlormadinonacetat distributed in a refatting basis, optionally in combination with a hydrophilic component molecularly dispersed , is present.

12. A pharmaceutical or cosmetic composition according to any one of claims 7 to 11, characterized in that the composition contains a penetration promoter, preferably a compound selected from the group comprising acid amides and / or amines.

13. A pharmaceutical or cosmetic composition according to any one of claims 7 to 12, characterized in that the composition contains at least one dye and / or a fragrance.

14. A pharmaceutical composition according to any one of claims 7 to 13, suitable for at least once a day, topical treatment of the human skin, preferably the scalp, facial skin, the upper body, the skin of the back and / or chest, and optionally the hair.

15. Cosmetic composition according to one of claims 7 to 13, suitable for at least once a day care of the human skin, preferably the scalp, facial skin, the upper body, the skin of the back and / or chest, and optionally the hair.

16. Use of a cosmetic composition according to any one of claims 7-13, for the prevention and / or use in seborrhea and / or acne, preferably acne vulgaris, androgenetic alopecia and / or to promote hair growth in both female and male patients.