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INVENTION
Russian Federation Patent RU2238083

Treatment of chronic eczema skin of hands

Treatment of chronic eczema skin of hands

Name of the inventor: Werner Bollag (CH); OTT Fritz (CH)
The name of the patentee: Basilea Farmatsoytika AG (CH)
Patent Attorney: Veselitskaya Irina
Address for correspondence: 101000, Moscow, M.Zlatoustinsky Lane, 10, kv.15, "EVROMARKPAT" pat.pov.. N.N.Pivnitskoy
Starting date of the patent: 1998.08.18

The invention relates to medicine, particularly to immunology and dermatology, and can be used for the treatment of chronic hand eczema skin. For this proposed use of 9-cis retinoic acid or its pharmaceutically acceptable salts or hydrolyzable esters for the manufacture of a medicament for the treatment of said disease. Thus formulations for topical and oral administration may be used. Unlike other retinoids 9-cis-retinoic acid provides a highly efficient treatment of skin eczema hands and safety of this treatment.

DESCRIPTION OF THE INVENTION

The present invention relates to the use of 9-cis retinoic acid and derivatives or precursors thereof for the manufacture of a medicament for the treatment of immune diseases mediated by T-helper type 1 cells, but also to the use of said active substances for the treatment of such diseases.

Despite intensive research retinoids clinically for the past 27 years, it has been found that their use in such a clinical setting is appropriate for the treatment of diseases mediated by immune factors. Currently, there are no data on the sensitivity of retinoids to a disease associated with cellular immunity mediated by T-helper cells type 1 (Th1), and diseases associated with humoral immunity, mediated by T-helper cell type 2 (Th2). The classification into Th1 dependent diseases, such as autoimmune and other cell-mediated immune diseases such as rheumatoid arthritis, multiple sclerosis, uveoretinitis, thyroiditis, Crohn's disease, insulin dependent diabetes mellitus, eczema, systemic lupus erythematosus, a and rejection of allogeneic organ transplants and Th2 -dependent immune diseases, i.e. diseases with dominant humoral or antibody-mediated factor, such as allergic diseases, such as atopic dermatitis, allergic rhinitis, hay fever and allergic bronchial asthma, corresponds to the classification proposed Romagnani et al., Th1 and Th2 Cells in Health and Disease, Chem. Immunol, Karger, Basel, 63, and str.158-170 187-203 (1996).

The inventors for the first time unexpectedly found that retinoid, namely 9-cis retinoic acid and its salts, esters and metabolic precursors or prodrugs and and metabolites of 9-cis retinoic acid, such as 4-oxo-9-cis retinoic acid, are effective in the treatment of clinical conditions Th1 - dependent diseases.

As used herein, the term "metabolic precursors or prodrugs and and metabolites of 9-cis retinoic acid" refers to compounds that are converted into 9-cis retinoic acid metabolism, and it is, in particular, it comprises 9-cis-retinal and 9-cis retinol and pharmaceutically acceptable acetals of 9-cis retinal and pharmaceutically acceptable hydrolyzable esters of 9-cis-retinol, and and metabolites of 9-cis retinoic acid, such as 4-oxo-9-cis-retinoic acid or its glucuronides.

According to the invention it has been found that administration of 9-cis retinoic acid, its pharmaceutically acceptable salts and pharmaceutically acceptable hydrolyzable esters, 9-cis retinal and pharmaceutically acceptable acetals, 9-cis retinol and pharmaceutically acceptable hydrolyzable esters, and and metabolites of 9-cis retinoic acid is effective in treating patients with diseases mediated by T-helper cells type 1 (Th1).

The invention thus relates to the use of 9-cis retinoic acid, its pharmaceutically acceptable salts or pharmaceutically acceptable hydrolyzable ester of 9-cis retinal or a pharmaceutically acceptable acetal or 9-cis retinol or a pharmaceutically acceptable hydrolyzable ester thereof, a and metabolites of 9-cis retinoic acid for the preparation of a medicament for the treatment of immune diseases mediated by T-helper cells type 1 (Th1).

The invention and a method of treating patients with immune diseases mediated by T-helper cells type 1 (Th1), comprising administering to said human patient a compound selected from the group consisting of 9-cis retinoic acid, its pharmaceutically acceptable salts and pharmaceutically acceptable hydrolyzable esters, 9-cis retinal and pharmaceutically acceptable acetals, and 9-cis retinol and pharmaceutically acceptable hydrolyzable esters and and metabolites of 9-cis retinoic acid, the compound is administered in an amount effective to treat said disease.

As used herein, the term "disease mediated by T-helper cell type 1 (Th1)" refers to diseases other than the dominant cellular immune response, and it is, in particular, include autoimmune and other cell-mediated immune diseases such as rheumatoid arthritis, multiple sclerosis , uveoretinitis, thyroiditis, Crohn's disease, insulin-dependent diabetes mellitus, eczema, systemic lupus erythematosus and allogeneic graft rejection and (e.g. rejection of allogeneic skin grafts, kidney, heart, lung or liver). The term "eczema" relates, in particular, to eczema due to delayed type hypersensitivity. The term "treatment" or "treating" includes preventive and / or therapeutic treatment.

9-cis retinoic acid and its derivatives and metabolic precursors and prodrugs and and metabolites of 9-cis-retinoic acid when administered to patients are effective, in particular for the treatment of diseases mediated by T-helper type 1 (Th1) cells as rheumatoid arthritis, multiple sclerosis, uveoretinitis, thyroiditis, Crohn's disease, insulin-dependent diabetes mellitus, systemic lupus erythematosus, a and eczema, including various classes of exogenous eczema, such as irritant dermatitis, allergic contact dermatitis, tileznaya eczema or "Aqueous" endogenous eczema, such as seborrheic dermatitis (and called seborrheic dermatitis or associated with lesions seborrhea dermatitis), kserodermalnaya eczema and discoid eczema, and eczemas localized at various sites of the body. 9-cis retinoic acid and its derivatives and metabolic precursors and prodrugs are effective in all those immune diseases which might be somehow linked with an increase of Th1 cell activity and increased secretion of the related cytokines, i.e. interleukin-12, interleukin-2, U-interferon and a, b of the tumor necrosis factor.

For the treatment of Th1-mediated diseases other than eczema active agent, i.e. 9-cis retinoic acid, its pharmaceutically acceptable salt or a pharmaceutically acceptable hydrolyzable ester thereof, 9-cis retinal or a pharmaceutically acceptable acetal thereof or 9-cis retinol or a pharmaceutically acceptable hydrolyzable ester thereof or metabolites of 9-cis-retinoic acid administered orally. active substances for the treatment of eczema used either orally or topically. Preferably, said compound is administered as a composition containing said active compound and a pharmaceutically acceptable carrier or diluent compatible with said active compound. Any conventional pharmaceutical acceptable carrier may be used for preparing such a composition. When the drug is administered orally, generally, it is administered at regular intervals, conveniently at mealtimes or once daily. It was found that this compound is effective in doses which show no or only mild side effects when given orally or when given topically. Therefore, oral administration of active compound is generally preferred. However, the treatment of eczema and advantageously may be applied topically applying.

In the treatment of immune diseases mediated by T-helper cells type 1, 9-cis-retinoic acid and its derivatives and metabolic precursors and prodrugs as well and its metabolites when administered orally have therapeutic efficacy at doses that do not cause side effects or only such weak side effects, such as dry lips and transient headache. All currently known retinoids exhibiting therapeutic effects in dermatological and oncological indications have to be administered orally in doses which induce more or less marked side effects belonging to the toxic syndrome characteristic of hypervitaminosis A, such as disturbances of skin and mucous membranes, musculoskeletal and neurologic disorders, in particular headache. Furthermore, they cause a detectable laboratory abnormalities such as increased transaminases (ALAT (alanine aminotransferase), ASAT (aspartate aminotransferase)), increased levels of alkaline phosphatase and increased levels of triglycerides and cholesterol and. In contrast, the daily doses of 9-cis retinoic acid, its derivatives and metabolic precursors and prodrugs and metabolites of 9-cis retinoic acid (typically 20 to 60 mg) therapeutically efficacious against immune diseases mediated by T-helper cells type 1, produce only very slight side effects, such as dry lips and transient headache, and cause all the other toxic signs and symptoms characteristic of hypervitaminosis a syndrome, including the laboratory abnormalities detected conditions.

It should be noted that the same low daily doses of 9-cis-retinoic acid does not have a therapeutic effect on non-malignant skin disorders such as acne, psoriasis, lamellar ichthyosis, Darier's disease and lichen planus. In general it was found that the very well tolerated low daily doses of 20 to 60 mg of 9-cis retinoic acid (and its derivatives and metabolic precursors and prodrugs) are efficacious in the treatment of immune diseases mediated by T-helper cells type 1, then whereas such doses are not efficacious in the treatment of non-malignant skin disorders, such as acne, psoriasis and other keratinizing dermatoses associated. With regard to malignant skin diseases and solid tumors of other organs, even high oral daily doses of 9-cis retinoic acid of up to 300 mg, inducing marked to severe side effects, did not lead to a significant regression of tumors.

In the treatment of immune diseases mediated by T hellernymi cell type 1, 9-cis retinoic acid, its pharmaceutically acceptable salt or a pharmaceutically acceptable hydrolyzable ester thereof, 9-cis retinal or a pharmaceutically acceptable acetal thereof or 9-cis retinol or a pharmaceutically acceptable hydrolysable ester thereof or metabolites of 9-cis retinoic acid can be used alone or in combination with other agents, such as in combination with other pharmaceutically active substances such as topical or systemic corticosteroids and other immunosuppressive agents (cytostatics, antimetabolites, biological response modifiers, e.g. interferons, interleukins and other cytokines). When used in combination with other substances, 9-cis-retinoic acid, or derivatives thereof, or metabolic precursor or prodrug or its metabolites and said other substance can be administered alone or preferably may be incorporated in effective amounts into one pharmaceutical composition.

As used herein, the term "pharmaceutically acceptable salts" includes any salt, for which in the art knows that it is chemically compatible with the 9-cis retinoic acid can be administered to human patients in a pharmaceutically acceptable composition. It can be used any such conventional pharmaceutically acceptable salt of 9-cis retinoic acid. Among the conventional salts which can be used, it should be mentioned salts with bases, for example alkali metal salts such as sodium or potassium salts, alkaline earth metal such as calcium or magnesium salts, and ammonium or alkylammonium salts.

According to the present invention, 9-cis retinoic acid can be administered in the form of pharmaceutically acceptable hydrolyzable esters. Any pharmaceutically acceptable hydrolyzable ester can be used in the compositions and methods of the invention. Among the preferred esters should be mentioned aromatic esters such as benzyl esters in which the benzyl moiety may be unsubstituted or may be substituted (lower alkyl.) Alkyl, halo, nitro, thio or substituted thio, or (lower alkyl.) Alkyl esters, e.g. ethyl, t-butyl, cyclopentyl, cyclohexyl or cycloheptyl ester, or 9-fluorenilmetilovy ether.

As used herein, the term "alkyl" refers to alkyl radicals having a straight chain, branched chain or cyclic, particularly residues containing from 1 to 12 carbon atoms such as methyl, ethyl, propyl, isopropyl, tert-butyl, decyl, dodecyl , cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "(lower). Alkyl" means alkyl groups containing from 1 to 7 carbon atoms.

According to the present invention, in an alternative embodiment, instead of 9-cis retinoic acid in the compositions and methods of the invention can be applied metabolic precursor or prodrug of 9-cis retinoic acid or metabolites of 9-cis retinoic acid, in particular 9-cis-retinal, 9 cis retinol, a pharmaceutically acceptable acetal of 9-cis retinal and pharmaceutically acceptable hydrolyzable esters of 9-cis retinal and any pharmaceutically acceptable acetal of 9-cis retinal and any pharmaceutically acceptable hydrolyzable ester of 9-cis-retinol or 4 - oxo-9-cis-retinoic acid. Among the preferred acetals of retinal are dialkyl acetals mentioned, especially di (lower. Alkyl), such as the diethyl acetal, and dibenzyl acetals, wherein the benzyl moieties are unsubstituted or may be substituted (lower alkyl.) Alkyl, halo, nitro, thio, or substituted thio. Among the preferred hydrolyzable esters of 9-cis retinol should be mentioned esters formed with C1-C20 carboxylic acids, such as C 1 -C 20 alkanoic acid and C 1 -C 20 alkenoic acids; particularly preferred esters are esters of carboxylic acids which contain a carboxylic acid moiety is an even number of carbon atoms, such as acetate, stearate or palmitate.

The aforementioned 9-cis retinoic acid and its salts, its esters and its metabolic precursors or prodrugs as well and its metabolites are useful especially in pharmaceutically acceptable form for oral administration or topical application. These pharmaceutical compositions contain said compound in association with a compatible pharmaceutically acceptable carrier. They can be used any conventional carriers. The carriers may be organic or inorganic inert carrier material suitable for oral administration. Suitable carriers include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, etc. Pharmaceutically active preparations may contain other pharmaceutically active agents. Furthermore, according to the accepted practice of the preparation of pharmaceutical compositions may be administered additives such as flavoring agents, preservatives, stabilizers, emulsifiers, buffers, etc.

The pharmaceutical compositions may be formulated in any conventional form including inter alia (a) a solid form for oral administration such as tablets, capsules (e.g. gelatine capsules with a solid or liquid coated), pills, sachets, powders, granules and the like. p., and (b) preparations for topical administrations such as solutions, suspensions, ointments, creams, gels, micronized powders, aerosols, etc. The pharmaceutical compositions may be sterilized and / or may contain adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, salts for varying the osmotic pressure and / or buffers.

For topical application to the skin or mucous membrane the aforementioned derivative is preferably prepared as ointments, tinctures, creams, gels, solutions, lotions, sprays, suspensions, shampoos, hair soaps, perfumes and the like In fact, according to the present invention may be used any conventional composition. For use with the preferred embodiments of the method a composition comprising an agent of the present invention, has the form of an ointment, cream or lotion. A pharmaceutical composition for topical application to the skin can be prepared by mixing the aforementioned active ingredient with non-toxic, therapeutically inert, solid or liquid carriers customarily used in such compositions. These compositions usually contain at least about 0.0005 wt.%, Preferably from 0.0005 to 0.05, and more preferably from about 0.001 to 0.01 wt.% Active ingredient (i.e. 9-cis -retinoevoy acid or its derivative or its metabolic precursor or prodrug or metabolites) based upon the total weight of the composition. Since toxicity and irritancy of the active ingredient vary with the type of tissue (normal or diseased tissue) to which it is applied, it is often used in compositions for topical application in amounts up to 0.15 wt.% Or even higher quantities. and these compositions are preferably applied to the skin once or twice per day. These compositions can be used depending on the needs of the patient. In practicing the present invention, the active substance can be applied as an aqueous solution or an alcohol solution such as ethanol.

In making the compositions described above for topical administration may be used adjuvants such as preservatives, thickeners, perfumes and the like which are commonly used in the art of pharmaceutical formulation for topical application. In addition, topical compositions containing the aforementioned active agent, conventional antioxidants or mixtures of conventional antioxidants can be incorporated. From the conventional antioxidants which can be used in these compositions, one should note N-methyl- -tokoferolamin, tocopherols, butylated hydroxyanisole, butylated hydroxytoluene, ethoxyquin and the like Cream-base pharmaceutical formulations containing the active agent and which are used according to the invention are aqueous emulsions containing a fatty acid alcohol, semi-solid petroleum hydrocarbon, ethylene glycol and an emulsifying agent.

Compositions in the form of ointments containing the active ingredient of the invention include mixtures of semi-solid petroleum hydrocarbon with a dispersion of active compound in a solvent. Containing the active cream composition substance for use according to the present invention are preferably emulsion consisting of the aqueous phase of a humectant, a viscosity stabilizer and water, an oil phase consisting of a fatty acid alcohol, a semisolid petroleum hydrocarbon and an emulsifying agent and a phase containing the active agent dispersed in an aqueous stabilizer-buffer. The composition for topical application stabilizers may be added. According to the present invention may be used any conventional stabilizers. The oil phase component constituting the fatty acid alcohol function as a stabilizer. These components represent a fatty acid alcohol obtained after reduction of saturated fatty acids with a long chain containing at least about 14 carbon atoms. Furthermore, according to the present invention can be used conventional perfumes and lotions generally used in a composition intended for topical application to the hair. Furthermore, if necessary, in the compositions for topical use in the invention may be used conventional emulsifiers.

Preferred oral dosage forms are tablets, pills, sachets, or capsules coated with hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. Each tablet, pill, sachet or capsule can preferably contain from about 5 to about 50 mg, more preferably from about 10 to about 20 mg of active substance. The doses for oral administration, which are discussed according to the present invention will vary according to the needs of the individual patient as determined by the attending physician. However, as a rule, the daily dose is from about 0.05 mg to about 1.5 mg per kg of body weight, and preferably from about 0.3 mg to about 0.9 mg per kg body weight of the patient. This dose may be administered using any dosage schedule determined by the physician which is in accordance with the needs of the patient.

Daily oral doses of between about 0.05 mg to about 1.5 mg per kg of body weight, and preferably from about 0.3 mg to about 0.9 mg per kg of body weight are administered either continuously or on an intermittent dosage schedule for example in the form of repetitive cycles, according to which the treatment is carried out 3 days a week and performed 4 days per week, or alternatively in the form of cycles, according to which the treatment is carried out 7 days and 7 days is not carried out. To maintain a sufficiently high level in plasma or blood may be necessary to abandon concurrent therapy cytochrome P450 isoenzyme inducers and / or by adding inhibitors of cytochrome P450 isoenzymes. Scheme application depend on the type of Th1-mediated immune disease such as eczema, rheumatoid arthritis, multiple sclerosis or Crohn's disease, but also on the stage of the disease, levels of 9-cis retinoic acid in blood plasma and, concomitant drug therapy and the patient's condition. Therapy with 9-cis retinoic acid can be used as continuous daily treatment or in the form of intermittent application of the scheme as described above. Therapy with 9-cis-retinoic acid and may be in the form of continuous treatment inducing treatment until remission, followed by treatment of intermittent schedule as a maintenance therapy.

Treatment with 9-cis retinoic acid can be combined with other drugs for the treatment of Th1-mediated diseases such as rheumatoid arthritis, multiple sclerosis or Crohn's disease. Such drugs include, for example, methotrexate, azatioprim, corticosteroids, cyclosporine, mycophenolate mofetil or interferons, for example interferon - b.

Dose for the treatment typically depends on the route of administration, age, weight and disease condition of the individual. Suitable dosage forms are known in the art or can be readily prepared by well-known manner. Formulations of lotions, gels, creams, hard gelatin capsules or soft coated tablets and sachets that are most suitable for use according to the present invention or that can easily be prepared according to the above description, it is suggested for example in US 5,428,071.

In a preferred embodiment, the treatment of eczematoid conditions is carried out orally or topically.

In one embodiment, the present invention relates to a method for the treatment of eczematoid condition in a human patient suffering from said condition comprising the oral administration or administration to said patient 9-cis retinoic acid in an amount sufficient to treat a condition of said patient. Suffering active form of eczema patients are treated to reduce the severity of injuries caused by eczema or other symptoms. In the case where a patient previously had damage caused by the active form of eczema, which is in a state of remission, the invention provides prophylactic treatment helps to prevent recurrence of active manifestations of eczema. According to the present invention, any eczematoid condition can be treated manner described. Examples of the active phase and remission phase eczematous conditions that are amenable to treatment include acute and chronic irritant dermatitis, allergic contact dermatitis, eczema or tileznuyu "Aqueous", seborrheic eczema, eczema kserodermalnuyu and discoid eczema.

9-cis retinoic acid can be administered orally in any amount effective in the treatment of eczematoid conditions. For example, preferred use of 9-cis retinoic acid or its precursor based upon administration of from about 0.3 to about 0.9 mg of 9-cis retinoic acid per kilogram of body weight. This dose may be administered according to any dosage schedule determined by the physician in accordance with the patient's needs. In specific embodiments, oral daily doses from about 0.3 to about 0.9 mg per kg of body weight are administered either continuously or on an intermittent dosage schedule, for example in the form of repetitive cycles, according to which the treatment is carried out 3 days a week and performed 4 days per week, or alternatively in the form of cycles, according to which the treatment is carried out 7 days and 7 days is not carried out. Therapy with 9-cis-retinoic acid and may be in the form of continuous treatment inducing treatment until remission, followed by treatment of intermittent schedule as a maintenance therapy.

For treatment of eczematoid conditions by the oral administration of 9-cis retinoic acid last patient orally administered as a composition containing 9-cis retinoic acid or a precursor which gives the 9-cis-retinoic acid, or converted into it. Examples of suitable precursors of 9-cis retinoic acid include pharmaceutically acceptable salts of 9-cis retinoic acid, hydrolyzable esters of 9-cis retinoic acid, 9-cis retinal, hydrolyzable esters 9-cis retinal, 9-cis-retinol and hydrolyzable esters of 9-cis-retinol.

In one embodiment, a method for treating eczematous conditions with drugs for oral administration, the composition containing 9-cis retinoic acid or its precursor, is in a unit oral dose. In a more specific embodiment, the standard oral dose is a tablet, capsule, pill or sachet containing 5 to 50 mg, preferably 10 to 20 mg of 9-cis retinoic acid or its pharmaceutically acceptable salt or its hydrolyzable ester.

Pharmaceutically acceptable salts include any salt chemically compatible with the 9-cis retinoic acid and suitable for administration to human patients in a pharmaceutically acceptable composition. It can be used any conventional pharmaceutically acceptable salt of 9-cis retinoic acid. Among the conventional salts which can be used, it should be mentioned salts with bases, for example alkali metal salts such as sodium or potassium salts, alkaline earth metals such as calcium or magnesium salts, and ammonium or alkylammonium salts.

The compositions and method of pharmaceutically acceptable hydrolyzable esters can be used according to the invention. Among the aromatic esters should be mentioned ethers such as benzyl (OBzl) or benzyl substituted (lower alkyl.) Alkyl, halo, nitro, thio or substituted thio, i.e. (Lower). Alkilotiogruppoy (comprising 1-7 carbon atoms), aliphatic esters such as (lower alkyl.) Alkyl, tert-butyl, cyclopentyl, cyclohexyl and cycloheptyl esters and 9-fluorenmetilovy ether.

In another embodiment, the present invention relates to a method for the treatment of eczematous skin condition in a human patient in need of such treatment which comprises topically applying to the patient's skin affected by said condition 9-cis retinoic acid in an amount effective against facilitate this state . Suffering active form of eczema patients are treated to reduce the severity of injuries caused by eczema or other symptoms. In the case where a patient previously had damage caused by the active form of eczema, which is in a state of remission, the invention provides prophylactic treatment helps to prevent recurrence of active manifestations of eczema. According to the present invention, any eczematoid condition can be treated manner described. Examples of the active phase and remission phase eczematous conditions that can be treated include irritant dermatitis, allergic contact dermatitis, eczema or tileznuyu "Aqueous", seborrheic eczema, eczema kserodermalnuyu and discoid eczema.

For treatment of eczematoid conditions in a patient by topical 9-cis-retinoic acid is applied last by topical application in the form of a composition for topical application comprising a compound selected from 9-cis retinoic acid and dermatologically acceptable salts thereof. In the preparation of these compositions for topical administration, the compound, a pharmaceutically acceptable salt or pharmaceutically acceptable esters thereof are mixed with a pharmaceutically acceptable carrier for topical application. Any conventional carrier may be used according to the present invention.

These topical compositions which contain 9-cis retinoic acid and its salts and may include any conventional excipients and additives commonly used to prepare topical compositions. Among the conventional additives or excipients which can be used for the preparation of the compositions according to the present invention, it should be noted preservatives, thickeners, perfumes, etc. In addition, these compositions may include conventional antioxidants such as butylated hydroxyanisole (BHA), ascorbyl palmitate, propyl gallate, citric acid, butylated hydroxytoluene (BHT), ethoxyquin, tocopherol, etc. These topical compositions can contain conventional acceptable carriers adapted for topical application which are commonly used in these compositions. These compositions may contain thickening agents, humectants, emulsifiers and viscosity stabilizers, which are generally used in such forms. Moreover, these compositions can contain colorants and perfumes which are conventional in preparing cosmetic compositions.

A composition for topical application can contain any concentration of 9-cis retinoic acid or its salt which is effective in the treatment of eczematoid conditions. For example, the composition may be used which contains a compound in a concentration from about 0.001 to about 0.05% by weight of the composition. More specific concentrations of compounds that are suitable in the method include from about 0.003 to about 0.03% by weight of the composition, and from about 0.005 to about 0.01% by weight of the composition. Other suitable concentrations of the compound are at least about 0.0005 wt.%; from 0.0005 to 0.15 wt.%, from 0.005 to 0.001 and 0.05 to 0.01% by weight of the composition.

Pharmaceutically acceptable salts include any salt chemically compatible with the 9-cis retinoic acid and suitable for use in the treatment of human patients in a pharmaceutically acceptable composition. It can be used any conventional pharmaceutically acceptable salt of 9-cis retinoic acid. Among the conventional salts which can be used, it should be mentioned salts with bases, for example alkali metal salts such as sodium or potassium salts, alkaline earth metal such as calcium or magnesium salts, and ammonium or alkylammonium salts.

The topical composition may be in any form which is generally used for compositions intended for topical application. For example, a composition for topical application can be in the form of an ointment, cream, gel, lotion or shampoo. Other examples of shapes, suitable for compositions intended for topical application include tinctures, solutions, suspensions, micronized powders, soaps, perfumes and aerosols.

The following examples illustrate the invention without limiting its scope.

example 1

Activity of 9-cis-retinoic acid against chronic hand eczema

a) Methodology

Fifteen patients, eight men and seven women, with chronic hand eczema, refractory to conventional treatment, were treated with 9-cis retinoic acid. The average age of patients was 52.3 years, range from 21 to 83 years. Before therapy with 9-cis retinoic acid eczema had already lasted for 3 months to 8 years, with an average of 29 months. Besides avoidance of irritants and allergens, their previous treatment consisted in topical application intended for this use of corticosteroids (15 patients), topical application of tar (2 patients), isotretinoin (2 patients), tretinoin (1 patient) and X-rays (3 patients) . The response to these treatments was in all cases unsatisfactory, in 4 patients in this medium, in 3 patients and poor 8 patients had no response to treatment. Therapy consisted in a once daily with breakfast 9-cis retinoic acid in a dose of 40 mg in the form of two soft gelatin capsules, coated, containing 20 mg of 9-cis retinoic acid. Eight patients received in the first week only 20 mg. The average duration of treatment was 2 months, range from 1 to 3 months. To assess the therapeutic effect of such the following lesions and symptoms such as erythema, papules and vesicles, desquamation, hyperkeratosis, cracking and itching / pain was evaluated on a scale from 0 to 4 (0 means no symptoms, 1 denotes mild symptoms, 2 denotes the average symptoms and 4 is severe symptoms). Evaluated side effects, in particular related to the syndrome of hypervitaminosis A: headache, dry mouth, and other disorders of skin and mucous membranes, symptoms associated with skeletal muscle, and anomalies detected in laboratory conditions.

b) Results

As seen from Table 1, all fifteen patients responded markedly to treatment with 9-cis retinoic acid (9-cis-RA) and all the various lesions and symptoms were improved by the treatment. The total damage score / symptoms in 14-responder patients has decreased by an average of 81.3% (range 53-100%). It found a beneficial effect on all the various lesions and symptoms such as erythema, papules and vesicles etc., which decreased by 62-100%. 9-cis-retinoic acid at a dose of 40 mg daily was very well tolerated. The only side effects found in these 15 patients were shown to rapidly passing headache in 2, and dry lips in 5 patients. It revealed no violations mucocutaneous detected at higher doses, and no symptoms associated with a musculoskeletal or other symptoms. Such symptoms were detected at higher doses (Kurie et al, Clin Cancer Res, 2, 287-293 (1996);..... Miller et al, Clin Cancer Res, 2, 471-475 (1996)). . At this low dosage of 9-cis retinoic acid is not found in well known laboratory revealed abnormalities such as increased transaminases levels (ALAT, ASAT), alkaline phosphatase increase, but also increase the level of triglycerides and cholesterol, frequently caused by retinoids. The response to the therapy with 9-cis retinoic acid in patients chronic hand eczema, refractory to conventional treatment, the physician assessment, but also the patient was very good or good in 13 of 15 patients or 87% of the patients (Tables 1 and 2).

CLAIM

1. The use of 9-cis retinoic acid and its pharmaceutically acceptable salts and pharmaceutically acceptable hydrolyzable esters thereof as active ingredient for the manufacture of a medicament for the treatment of chronic hand eczema skin.

2. Use according to claim 1, wherein the active substance is used in combination with a pharmaceutically acceptable carrier.

3. Use according to claim 1 or 2, wherein the medicament is manufactured for oral or topical administration.

4. Use according to any one of claims 1-3, wherein the medicament is manufactured as a tablet, capsule, pill, sachet, ointment, cream or lotion.

5. Use according to any one of claims 1-4, wherein the medicament is prepared in form of tablets, capsules, pills, cachets, and which contain from 5 to 50 mg, preferably 10-20 mg of active substance.

6. Use according to any one of claims 1-5, wherein the medicament is prepared in a daily dose of oral administration, comprising from 0.05 mg to 1.5 mg, preferably 0.3 to 0.9 mg per kg body weight.

7. Use according to any of claims 1-6 wherein the medicament is manufactured as an ointment, cream or lotion which contains from 0.0005 to 0.05 wt.%, Preferably from 0.001 to 0.1 wt.% Of active substance .

8. Use according to any one of claims 1-7, wherein the active substance is selected from the group consisting of 9-cis retinoic acid and its alkali metal salts, alkaline earth metal salts, its esters, benzyl, (lower) alkyl esters of 9- fluorenilmetilovye esters.

9. Use according to claims 1-8, wherein the active ingredient is 9-cis-retinoic acid or a pharmaceutically acceptable salt thereof.

10. The use of 9-cis retinoic acid for the manufacture of a medicament for the treatment of chronic hand eczema skin.

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Publication date 01.04.2007gg