EP1735001A2

EP1735001A2 - Pharmaceutical compositions for the treatment of skin diseases comprising a combination of epinastine and one or more additional minerals or one or more crude drugs

Info

Publication number: EP1735001A2
Application number: EP05716230A
Authority: EP
Inventors: Tetsuo Hayashi; Shinichiro Katsuyama; Minoru Okada; Norimitsu Umehara
Original assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG; Boehringer Ingelheim Pharmaceuticals Inc
Current assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG; Boehringer Ingelheim Pharmaceuticals Inc
Priority date: 2004-03-24
Filing date: 2005-03-19
Publication date: 2006-12-27
Also published as: PE20051158A1; WO2005089803A2; JP2007530481A; AR049876A1; WO2005089803A3

Abstract

The present invention relates to pharmaceutical compositions for the treatment of skin diseases. Particularly, the compositions described in the present invention are highly effective for the treatment of skin diseases associated with allergic reactions among a variety of symptoms derived from skin diseases. These compositions comprise an antihistaminic-effective amount of epinastine or a pharmaceutically acceptable salt thereof and one or more additional pharmaceutically acceptable minerals or one or more pharmaceutically acceptable crude drugs. The compositions may also comprise pharmaceutically acceptable additives.

Description

Pharmaceutical compositions for the treatment of skin diseases comprising a combination of epinastine and one or more additional minerals or one or more crude drugs

The present invention relates to pharmaceutical compositions for the treatment of skin diseases. Particularly, the compositions described in the present invention are highly effective for the treatment of skin diseases associated with allergic reactions among a variety of symptoms derived from skin diseases. In a first embodiment, these compositions comprise an antihistaminic-effective amount of epinastine or a pharmaceutically acceptable salt thereof and one or more additional pharmaceutically acceptable minerals as pharmacologically active compounds. In a second embodiment these compositions comprise an antihistaminic-effective amount of epinastine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable crude drugs as pharmacologically active compounds. The compositions may also comprise pharmaceutically acceptable additives.

Moreover, the present invention relates to the use of these compositions to treat symptoms such as pruritus (itching), derived from skin diseases such as urticaria, eczema, and skin irritation, prurigo and psoriasis vulgaris.

Background of the invention

In recent years, the incidence of developing skin diseases associated with allergic reactions has increased due to changes in diet and life style, air pollution, increased exposure to environmental chemicals due to various factors of deterioration in environmental conditions, and increased stress from the social life and so on. Among these skin diseases associated with allergic reactions are urticaria, eczema, skin irritation, and dermatitis. Skin disease accompanying itching represented by pruritus, prurigo, and psoriasis vulgaris are also prevailing in number.

Urticaria, a synonym of wheal, is a transient edema. The disease is characterized by a sudden onset of itchy sensation on skin, followed by developing well-defined eruption swelling up like weal and growing into a size of nail plate to palm exacerbated by scratching. Although the symptoms disappear within a couple of minutes to hours and may not leave any skin disorder, episodes of development into eruption are likely to recur. Causes of urticaria may include autosensitization, sensitizations associated with difficult menstruation, pregnancy, foods, medicines and insect stings, abnormal responses to heat, cold, mechanical stimuli and light, remote responses to bacterial infections, gastrointestinal, hepatic, and renal disease, an endocrinopathic involvement, and psychological factors.

Eczema or dermatitis is the most major skin disease, characterized by inflammatory response on skin. Eczema and dermatitis are often referred altogether as eczematous dermatitis group. The diseases are often caused by pathological interactions caused by external stimuli (numbers of chemicals, fragrances, metals, detergents, medicines, plants, bacteria, insects, sunlight, heat, cold, dryness), internal abnormalities (local abnormalities such as perspiration, abnormal sebum secretion, abnormal keratosis, and systemic abnormalities such as atopic disposition, infection site, digestive disorder, renal dysfunction, endocrine disturbance), and bodily condition. Eczematous dermatitis group includes contact dermatitis, atopic dermatitis, seborrheic dermatitis, nummular eczema, autosensitization dermatitis, and lichen simplex chronicus Nidal.

Housewives' eczema, keratodermia tylodes palmaris progressiva, diaper dermatitis, and photocontact dermatitis are classified as atypical contact dermatitis. In addition, the group may include diffuse neurodermatitis, stasis dermatitis, infectious eczematoid dermatitis, and perioral dermatitis. Broadly, it may also include radiodermatitis, scald (burn), and frostbite.

Pruritus is a disease characterized by an onset of itchy sensation (itching) on apparently normal skin. Range of affected lesion divides pruritus into general pruritus and localized pruritus. The disease is derived from a variety of causes, and often develops as a symptom of systemic disease.

Prurigo presents extreme itching and is papule or urticaria-like nodule that progress to chronic or recurrent disorder, and can be broadly classified into prurigo acuta including strophulus infantum, lichen urticatus, prurigo aestiralis, prurigo simplex acuta, prurigo subacuta such as prurigo simplex subacuta, and prurigo chronica including chronica multiformis, prurigo nodularis, prurigo hebra, and prurigo simplex chronica. Mechanisms of the pathogenesis are unrevealed. Insect sting in prurigo acuta, and diabetes mellitus, hepatopathy, leukemia, Hodgkin's disease, visceral cancer, and polycythemia in prurigo chronica are thought of as causatives.

Psoriasis vulgaris is an inflammatory skin disease, and presents histological characteristics of epidermal hyperplasia and inflammatory cellular infiltration. Eruption typically develops on head, extension side of extremities, and some parts of truncus which are in particular likely to come in contact with mechanical compression, in almost a half of which pruritus is observed. Immuno logical abnormalities may be concerned as a cause of disease.

It is emphasized that improving the surroundings such as elimination of causative antigens is the most important factor for the treatment of these skin diseases, particularly for allergic skin diseases. Nevertheless, as already reviewed, pathogenic causes are often fallible to be identified because they are varied and complicated. Therefore compositions combining antihistaminic compounds are of the frequent choice for treatment of these symptoms including itchy sensation caused from skin diseases.

Objective of the present invention

The present invention provides in a first embodiment pharmaceutical compositions and dosage forms comprising epinastine or a pharmaceutically acceptable salt thereof and one or more additional pharmaceutically acceptable minerals as pharmacologically active compounds for the prevention and/or treatment of skin diseases, preferably skin diseases associated with allergic reactions that exert its significant utility to achieve effective improvements.

The present invention provides furthermore pharmaceutical compositions and dosage forms comprising epinastine or a pharmaceutically acceptable salt thereof and one or more additional pharmaceutically acceptable crude drugs as pharmacologically active compounds for the prevention and/or treatment of skin diseases, preferably skin diseases associated with allergic reactions that exert its significant utility to achieve effective improvements.

The present invention furthermore provides a pharmaceutical pack comprising a pharmaceutical composition comprising epinastine or a pharmaceutically acceptable salt thereof as active agent and a pharmaceutical composition comprising one or more additional pharmaceutically acceptable minerals as pharmacologically active compound for joined or timely shifted administration, for the prevention and/or treatment of skin diseases, preferably skin diseases associated with allergic reactions that exert its significant utility to achieve effective improvements.

Additionally, the present invention provides a pharmaceutical pack comprising a pharmaceutical composition comprising epinastine or a pharmaceutically acceptable salt thereof as active agent and a pharmaceutical composition comprising one or more additional pharmaceutically acceptable crude drugs as pharmacologically active compound for joined or timely shifted administration, for the prevention and/or treatment of skin diseases, preferably skin diseases associated with allergic reactions that exert its significant utility to achieve effective improvements

In addition, the present invention provides the use of the above mentioned pharmaceutical compositions in the manufacture of a medicament for the treatment of skin diseases by employing highly effective pharmaceutical compounds for significant improvements on symptoms of skin disease accompanying itching, particularly urticaria, eczema, skin fit, dermatitis, pruritus, eruption, and psoriasis vulgaris accompanying itchy sensation.

Description of the invention

The present invention relates to pharmaceutical compositions, dosage forms and packs for the prevention and/or treatment of skin diseases, comprising an antihistaminic-effective amount of epinastine or its pharmaceutically acceptable salt thereof and one or more additional pharmaceutically acceptable minerals as pharmacologically active compounds.

The present invention relates furthermore to pharmaceutical compositions, dosage forms and packs for the prevention and/or treatment of skin diseases, comprising an antihistaminic- effective amount of epinastine or its pharmaceutically acceptable salt thereof and one or more additional pharmaceutically acceptable crude drugs as pharmacologically active compounds.

Epinastine, (±) 3 - amino - 9, 13b - dihydro - 1H - dibenz [c, f] imidazo [1,5-a] azepine, the hydrochloride thereof respectively, is a drug possessing Hi-antihistaminic properties. It primarily has been used to treat allergic reaction of the eyes and the nasal mucosa. The pharmaceutical compositions, dosage forms and packs of the present invention comprise epinastine in the form of a salt such as the hydrochloride, hydrobromide, oxalate, nitrate, sulfonate, fumarate, maleate, sulfate, and phosphate or the free base. Preferred is epinastine hydrochloride.

The amount of epinastine or a pharmacologically acceptable salt thereof depends on the application route.

In the case of oral administration, the daily dose of epinastine or a pharmacologically acceptable salt thereof in equivalent quantity to epinastine hydrochloride for an adult is about 2 to 20 mg per day, depending on the severity and stage of the disease, the weight of the patient and further parameters known to the skilled person. Preferred are daily doses of 5 to 15 mg, and particularly preferred are daily doses of 7.5 to 12.5 mg. The daily dose can be administered at one time per day (e.g. 1 tablet per day) or divided over the day, for example three times a day (e.g. 3 tablets three times daily). Correspondingly, the content of epinastine or a pharmacologically salt thereof in equivalent quantity to epinastine hydrochloride per dose unit for oral administration (e.g. tablet or capsule) is in the range of 0.2 to 20 mg, preferably 0.5 to 15, particularly preferred 0.75 to 12.5 mg.

In the case of topical administration, the dose in equivalent quantity to epinastine hydrochloride is in the range of 1 to 50 mg per 1 g of dosage form, preferably in the range from 2 to 30 mg per 1 g of dosage form, and more preferably in the range from 5 to 15 mg per 1 g of dosage form.

In one embodiment of the present invention the pharmaceutical compositions comprise an antihistaminic-effective amount of epinastine or a pharmaceutically acceptable salt thereof and one or more additional pharmaceutically acceptable minerals. Minerals in the meaning of the present invention are pharmaceutically acceptable compounds comprising one or more elements from the group consisting of calcium, zinc, iron, phosphorus, magnesium, potassium, copper, iodine, manganese, selenium, chromium, and molybdenum. One or more compounds of these minerals may be used to formulate this invention.

Minerals used in this invention may include synthetic compounds such as chemical synthetic compounds and enzymatic synthetic compounds, as well as natural products or its separated and purified form. No limitation is imposed on the form of mineral used in this embodiment of the present invention. Examples of the form may include mineral, salt, oxide, protein complex, complex of protein split product, polysaccharide complex, complex of polysaccharide split product, modified starch complex, cyclodextrin complex, metalloenzyme including minerals such as superoxide dismutase, glutathione peroxidase, and acid phosphatase, metal activating enzyme of phosphoglucomutase, enzyme or coenzyme including metal out side of the active center.

The preferred minerals in the meaning of this embodiment of the present invention are selected from the group consisting of: calcium gluconate, calcium hydrogen phosphate, dibasic calcium phosphate anhydrous, calcium glycerophosphate, calcium lactate, precipitated calcium carbonate, calcium chloride, calcium carbonate, calcium hydroxide, calcium citrate, calcium L-aspartate, calcium L-glutamate, calcium glycerophosphate, calcium 5'- ribonucleotide, calcium sulfate, tricalcium phosphate, calcium propionate, calcium dihydrogen phosphate (monobasic calcium phosphate), calcium dihydrogen pyrophosphate, carboxymethyl cellulose calcium, calcium stearoyl-2-lactylate, calcium oxide, zinc sulfate, zinc gluconate, zinc undecylenate, zinc oxide, zinc carbonate, zinc chloride, zinc yeast, iron, ferrous sulfate, ferric citrate, sodium ferrous citrate, ferrous gluconate, ferric pyrophosphate (Iron [El] Pyrophosphate), ferrous succinate, ferric chloride, ferrous lactate, saccharated ferric oxide, chondroitin sulfate/iron colloid, ferric ammonium citrate, iron oxide red (iron sesquioxide), ferritin, heme iron, phosphoric acid, potassium dihydrogen phosphate, potassium monophosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium diphosphate, sodium monophosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, calcium diphosphate, tricalcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, magnesium diphosphate, ammonium diphosphate, ammonium dihydrogen phosphate, diammonium hydrogen phosphate, pentapotassium triphosphate, sodium polyphosphate, sodium hexametaphosphate, tetrapotassium pyrophosphate, disodium dihydrogen pyrophosphate, tetrasodium pyrophosphate, magnesium carbonate, magnesium sulfate, magnesium citrate, magnesium lactate, magnesium chloride, magnesium oxide, magnesium aluminum silicate, magnesium aluminometasilicate, magnesium hydroxide aluminum, magnesium L-aspartate, magnesium L-glutamate, potassium chloride, potassium sulfate, potassium carbonate, potassium dihydrogen citrate, tripotassium citrate, potassium gluconate, potassium acetate, tripotassium phosphate, dipotassium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium hydroxide, aluminum potassium sulfate, potassium L- aspartate, monopotassium L-glutamate, copper sulfate, copper gluconate, sodium copper chlorophyllin, copper yeast, iodine, potassium iodide, sodium iodide, iodolecithine, manganese chloride, manganese sulfate, manganese yeast, sodium selenide, selenium disulfide, selenocysteine, selenomethionine, selenium yeast, chromium chloride, chromium yeast, sodium molybdate, molybdenum yeast.

In addition, compositions of this embodiment of the present invention may also include other pharmacologically active compositions such as antihistamines other than epinastine including diphenhydramine, chlorpheniramine, carbinoxamine, diphenylpyraline, and promethazine, antiphlogistics including glycyrrhizinic acid (glycyrrhizin), dipotassium glycyrrhizinate, potassium glycyrrhizinate, monoammonium glycyrrhizinate, di-ammonium glycyrrhizinate, glycyrrhetinic acid, and tranexamic acid, group B vitamins and vitamin-like active substances including vitamin Bi, vitamin B₆, vitamin B₁₂, niacin, pantothenic acid, biotin, folic acid, orotic acid, lipoic acid, p-aminobenzoic acid, inositol, carnitine, and choline, antioxidant vitamins and antioxidant vitamin-like substances including vitamin C, vitamin E, vitamin A, ubiquinone, pangamic acid, and flavonoid, sulfur containing amino acid including cysteine, methionine, aminoethyl sulfonic acid, and glutathione, and group D vitamins including ergocalciferol, and cholecalciferol.

Although the amount of the minerals to formulate this embodiment of the present invention varies depending on the type of mineral used, for oral use given daily to an adult, it lies about in the range from 0.3 μg to 4000 mg, and for topical use it lies about in the range from 0.1 mg/g to 8O0 mg/g.

In further details, combination amount of respective mineral to formulate this embodiment of the present invention for given daily to an adult are as follows:

Combination amount of calcium as calcium comprising mineral lies preferably in the range within 25O0 mg, more preferably in the range from 10 mg to 600 mg, most preferably in the range from 30 mg to 300 mg.

Combination amount of zinc as zinc comprising mineral lies preferably in the range within 30 mg, more preferably in the range from 0.02 mg to 24 mg, most preferably in the range from 0.12 mg to 12 mg. Combination amount of iron as iron comprising mineral lies preferably in the range within 40 mg, more preferably in the range from 0.01 mg to 20 mg, most preferably in the range from 0.1 mg to 10 mg.

Combination amount of phosphorus as phosphorus comprising mineral lies preferably in the range within 4000 mg, more preferably in the range from 1 mg to 2000 mg, most preferably in the range from 7 mg to 700 mg.

Combination amount of magnesium as magnesium comprising mineral lies preferably in the range within 700 mg, more preferably in the range from 1 mg to 640 mg, most preferably in the range from 3.2 mg to 320 mg.

_, Combination amount of potassium as potassium comprising mineral lies preferably in the . range within 4000 mg, more preferably in the range from 1 mg to 3000 mg, most preferably in the range from 2-mg to 2000 mg.

Combination amount of copper as copper comprising mineral lies preferably in the range within 9 mg, more preferably in the range from 0.001 mg to 3.6 mg, most preferably in the range from 0.01 mg to 1.8 mg.

Combination amount of iodine as iodine comprising mineral lies preferably in the range within 3 mg, more preferably in the range from 10 μg to 1000 μg, most preferably in the range from 1.5 μg to 150 μg.

Combination amount of manganese as manganese comprising mineral lies preferably in the range within 20 mg, more preferably in the range from 0.01 mg to 10 mg, most preferably in the range from 0.04 mg to 4 mg.

Combination amount of selenium as selenium comprising mineral lies preferably in the range within 250 μg, more preferably in the range from 0.01 μg to 150 μg, most preferably in the range from 0.5 μg to 55 μg. Combination amount of chromium as chromium comprising mineral lies preferably in the range within 250 μg, more preferably in the range from 0.01 μg to 150 μg, most preferably in the range from 0.3 μg to 35 μg.

Combination amount of molybdenum as molybdenum comprising mineral lies preferably in the range within 250 μg, more preferably in the range from 0.01 μg to 150 μg, most preferably in the range from 0.3 μg to 30 μg.

In addition, for topical use, the combination amount as mineral lies normally in the range within 800 mg/g, more preferably in the range from 0.1 mg/g to 500 mg/g, most preferably in the range from 0.45 mg/g to 450 mg/g of composition.

Especially preferred examples of minerals for oral use comprise calcium. It is preferable to use one or more calcium comprising minerals selected from calcium gluconate, calcium hydrogen phosphate, dibasic calcium phosphate anhydrous, calcium glycerophosphate, calcium lactate, and/or precipitated calcium carbonate. The amount of calcium to formulate the present invention given daily to an adult lies preferably in the range from 30 mg to 300 mg.

Especially preferred examples of minerals for topical use comprise zinc. It is particularly preferable to use one or more zinc comprising minerals selected from zinc oxide and/or zinc undecylenate. Zinc oxide may be used as zinc oxide starch powder. The amount of zinc lies preferably in the range from 0.45 mg/g to 450 mg/g of composition.

The pharmaceutical compositions described in this embodiment of the present invention may be orally given at once or in divided doses, and may be topically applied at once or in divided doses directly onto the affected legion of skin. Dose adjustment of epinastine and mineral may reflect age, body weight, and manifesting symptoms.

In a further embodiment the invention relates to pharmaceutical compositions for oral use providing for an rapid release of epinastine or a pharmaceutically acceptable salt thereof and providing for sustained release of all or a part of the one or more pharmaceutically acceptable minerals.

In addition, when the pharmaceutical compositions described in this embodiment of the present invention are orally given, a part of or all of the mineral, used as sustained release component, may be combined with the rapid release component of epinastine (or with epinastine and a part of the mineral). When a further additional active component is combined, said further active component may be divided into a sustained release component or a rapid release component according to the pharmacokinetic characteristic of each active component. These rapid release components and sustained release components may either be packaged in each dosing unit combining one another after being separately prepared as different formulations, or be prepared as a unit formulation. For example, rapid release tablet and sustained release tablet are packed for one package, or rapid release tablet and sustained release capsule are packed for one package. Unit formulations may include for example multilayer tablets combining rapid release layer(s) and sustained release layer(s), granules combining rapid release granules and sustained release granules or capsules filled with such granules, hard capsules filled with a combination of small rapid release tablet(s) and small sustained release tablet(s), and dry syrup or suspension syrup using microcapsules or -microspheres as sustained release components.

Such above mentioned multilayer tablets (e.g. bilayer tablets also referred to as two layer tablets), may provide for sustained release of all or a part of the one or more pharmaceutically acceptable minerals and for an rapid release of epinastine or a pharmaceutically acceptable salt thereof.

Such a two layer tablet may comprise a first layer A, providing for the rapid release of epinastine, containing epinastine or a pharmaceutically acceptable salt thereof and optionally a part of the pharmaceutically acceptable mineral and a second layer B, providing for the sustained release of the one or more minerals, containing all or a part of the one or more pharmaceutically acceptable minerals. The two layer tablet may additionally contain a tablet coating consisting of pharmaceutically acceptable excipients. Each layer of the two layer tablet is in contact with each other in a portion of their surface, but provides independent release profiles for both active substances mentioned before.

In another embodiment of the present invention the pharmaceutical compositions comprise an antihistaminic-effective amount of epinastine or a pharmaceutically acceptable salt thereof and one or more additional pharmaceutically acceptable crude drugs. Examples of crude drugs used in the present invention include fragrant wormwood flower (Artemisiae capillariflos), gardenia fruit (Gardeniae fructus), rhubarb (Rhei rhizoma), bupleurum root (Bupleuri radix), glehnia root (Glehniae radix cum rhizoma), poria sclerotium (Poria), cherry bark (Pruni jamasakura bark), platycodon root (Platycodi radix), ginger (Zingiberis rhizoma), aralia cordata root (Arali e cardatae rhizoma), schizonepeta spike (Schizonepetae spica), glycyrrhiza (Glycyrrhizae radix), coix seed (Coicis semen), smilax rhizome (Smilacis rhizoma), forsythia fruit (Forsythi e fructus), ground ivy herb (Glechomae herba), magnolia flower (Magnoliae flos), cnidium rhizome (cnidii rhizome). One or more these crude drugs may be used to formulate this invention. In addition, these crude drug can be dried powder, extract, fluidextract, ctincture, oil and etc.

In addition, compositions of this embodiment of the present invention may also include other pharmacologically active compositions such as pharmaceutically acceptable minerals including calcium, zinc, iron, phosphorus, magnesium, potassium, copper, iodine, manganese, selenium, chromium, and molybdenum comprising minerals, for example the minerals described above, antihistamines other than epinastine. including diphenhydramine, chlorpheniramine, carbinoxamine, diphenylpyraline, and promethazine, antiphlogistics including glycyrrhizinic acid (glycyrrhizin), dipotassium glycyrrhizinate, potassium glycyrrhizinate, monoammonium glycyrrhizinate, di-ammonium glycyrrhizinate, glycyrrhetinic acid, and tranexamic acid, group B vitamins and vitamin-like active substances including vitamin Bi, vitamin B₆, vitamin Bι₂, niacin, pantothenic acid, biotin, folic acid, orotic acid, lipoic acid, p-aminobenzoic acid, inositol, carnitine, and choline, antioxidant vitamins and antioxidant vitamin-like substances including vitamin C, vitamin E, vitamin A, ubiquinone, pangamic acid, and flavonoid, sulfur containing amino acid including cysteine, methionine, aminoethyl sulfonic acid, and glutathione, and group D vitamins including ergocalciferol, and cholecalciferol.

Although combination amount of the pharmaceutically acceptable crude drugs to formulate the present invention varies depending on the type of the crude drug used, for oral use given daily to an adult, it lies about in the range from 5 mg to 30000 mg as crude drug substance, and for topical use, it lies about in the range from 0.1 mg/g to 800 mg/g as crude drug substance.

In further details, combination amount of respective crude drug for oral use to formulate the present invention for given daily to an adult are as follows:

Combination amount of crude drug such as fragrant wormwood flower, ginger, glycyrrhiza and coix seed lies preferably in the range within 30000 mg, more preferably in the range from 15 mg to 20000 mg, most preferably in the range from 30 mg to 10000 mg as crude drug substance. Combination amount of crude drug such as gardenia fruit, rhubarb, bupleurum root, glehnia root, poria sclerotium, aralia cordata root, schizonepeta spike, smilax rhizome and ground ivy herb lies preferably in the range within 10000 mg, more preferably in the range from 10 mg to 7500 mg, most preferably in the range from 20 mg to 5000 mg as crude drug substance.

Combination amount of crude drug such as cherry bark, platycodon root and forsythia fruit lies preferably in the range within 5000 mg, more preferably in the range from 5 mg to 4000 mg, most preferably in the range from 10 mg to 2500 mg as crude drug substance.

In addition, for topical use, the combination amount as crude drug lies normally in the range from 0.1 mg/g to 800 mg/g, more preferably in the range from 0.1 mg/g to 500 mg/g, most preferably in the range from 0.45 mg/g to 450 mg/g as crude drug substance.

The pharmaceutical compositions of this embodiment of the present invention may be orally given at once or in divided doses, and topically applied at once or in divided doses directly onto the affected legion of skin. Dose adjustment of epinastine and crude drug may reflect age, body weight, and manifesting symptoms.

In a further embodiment the invention relates to pharmaceutical compositions for oral use providing for an rapid release of epinastine or a pharmaceutically acceptable salt thereof and providing for sustained release of all or a part of the one or more pharmaceutically acceptable crude drugs.

In addition, when the pharmaceutical compositions of this embodiment of the present invention are orally given, part of or all of the crude drug, used as sustained release component, may be combined with the rapid release component of epinastine (or with epinastine and part of crude drug). When further additional active component is combined, said further active component may be divided into sustained release component or rapid release component according to the pharmacokinetic characteristic of each active component.

These rapid release components and sustained release components may either be packaged in each dosing unit combining one another after being separately prepared as different formulations, or be prepared as a unit formulation. For example, rapid release tablet and sustained release tablet are packed for one package, or rapid release tablet and sustained release capsule are packed for one package. Unit formulations may include for example multilayer tablets combining rapid release layer(s) and sustained release layer(s), granules combining rapid release granules and sustained release granules or capsules filled with such granules, hard capsules filled with a combination of small rapid release tablet(s) and small sustained release tablet(s), and dry syrup or suspension syrup using microcapsules or microspheres as sustained release components.

The pharmaceutical compositions described in the present invention can be used in any oral form such as tablets, granules, fine granules, powders, capsules, caplets, soft capsules, pills, suspensions, emulsions, oral solutions, syrups, dried syrups, chewable forms, effervescent tablets, drops, and oral fast-dispersing tablets, and in any topical form such as creams, ointments, gel ointments, suppositories, poultices, tapes, topical solutions, aerosols, lotions, and foams. In addition, preparation formed into microparticles such as microcapsule, nanocapsules, microspheres, nanospheres, liposomes may be also included in the aforementioned compositions.

Such above mentioned multilayer tablets (e.g. bilayer tablets also referred to as two layer tablets), may provide for sustained release of all or a part of the one or more pharmaceutically acceptable crude drugs and for a rapid release of epinastine or a pharmaceutically acceptable salt thereof. Such a two layer tablet may comprise a first layer A, providing for the rapid release of epinastine, containing epinastine or a pharmaceutically acceptable salt thereof and optionally a part of the pharmaceutically acceptable crude drugs and a second layer B, providing for the sustained release of the one or more crude drugs, containing all or a part of the one or more pharmaceutically acceptable crude drugs. The two layer tablet may additionally contain a tablet coating consisting of pharmaceutically acceptable excipients. Each layer of the two layer tablet is in contact with each other in a portion of their surface, but provides independent release profiles for both active substances mentioned before.

Moreover, the properties of the compositions of the present invention such as stability, release, continuance, disintegration, distinglation, dissolution, concealment of taste, improvement in usage, etc. can be adjusted by addition of additives known in the art.

For example, the pharmaceutically active substance can be dispensed in separate granules, multi-layer granules, multi-layer tablets or dry coated tablets, tablets of separated granules, microcapsules, etc. Coating preparations such as sugar coated tablets, film coated tablets, coated granules, and effervescent tablets or effervescent granules can be included as well as chewable preparations, in the mouth dissolving preparations, matrix preparations, together with comminutions, solid solutions, etc. Sweetening agents, refrigerants, antioxidants or stabilizing agents, agents adjusting a certain pH- value can be added as well as agents influencing the viscosity, the osmotic pressure or the salt concentration. These methods can also be combined.

Optionally, the following additives also can be added: excipients, bases, binders, disintegrators, lubricants, superplasticizers, coating agents, sugar coating agents, plasticizers, antifoaming agents, polish, foaming agents, antistatic agents, desiccant, moisturizing agents, surfactant, solubilizer, buffer agents, resolvents, solubilizing agents, solvents, diluents, stabilizers, emulsifying agents, suspension, suspending agents, dispersing agents, isotonizing agents, aerosol propellant, adsorbents, reducing agents, antioxidant, backing, wetting agents, wet modifier, filler, extender, adhesives, viscous agent, softeners, pH modifiers, antiseptics, preservatives, sweetening agents, corrigent, refrigerative agents, flavoring agents, perfume, fragrance, coloring matters, etc. Any of these additives may be used in the regular composing methods, and no limitation is imposed on such composition methods.

The examples of these additives are explained in Japanese Pharmaceutical Excipients Directory 2000 (Japan Pharmaceutical Excipients Council edit, Yakuji Nippo. Ltd. issue).

These preparations can be manufactured in the usual manner, e.g. by adding preparation additives to the pharmacologically active substance.

The compositions described in the present invention are explained by examples which follow. However, the present invention of the pharmaceutical compositions is not limited to these examples. Examples

Example 1 : Tablet

The following ingredients were homogeneously mixed. The resulted mixed particles were compressed with a mold to prepare tablets of 300 mg each.

Epinastine hydrochloride 10 g Calcium gluconate 900 g Pyridoxine hydrochloride 22 g Lactose 200 g Microcrystalline cellulose 636 g Light anhydrous silicic acid 15 g Magnesium stearate 12 g Talc 5 g

Example 2 : Powder

The following ingredients were homogeneously mixed. The resulted mixed particles were divided into portions of 600 mg to prepare powder compositions.

Epinastine hydrochloride 5 g Calcium hydrogen phosphate 540 g Calcium lactate 363 g Corn starch 258 g Lactose 260 g Magnesium stearate 12 g

Example 3

: Two layer tablet

The following ingredients of A layer and B layer were processed through a regular method to provide mixed particles, respectively, and the particles were compressed to form two layer tablet of 300 mg (A layer 60 mg, B layer 240 mg) each.

A layer Epinastine hydrochloride 50 g Lactose 266 g Microcrystalline cellulose 272 g Light anhydrous silicic acid 6 g Talc 3 g Magnesium stearate 3 g B layer Calcium glycerophosphate 1200 g Dipotassium glycyrrhizinate 300 g Pyridoxine hydrochloride 60 g Lactose 700 g Hydro genated oil 50 g Hydro xypropylmethylcellulo se 2208 80 g Magnesium stearate 10 g

Example 4 : Oral solution

The following ingredients were dissolved in sterile purified water, added with sodium hydrate to adjust at pH 5, and diluted with sterile purified water to get a total volume of 20 L. The resulted solution was transferred in portions of 50 mL into glass bottles to provide oral solutions.

Epinastine hydrochloride 4 g Calcium gluconate 400 g Potassium L-aspartate 40 g Magnesium L-aspartate 40 g Ferric ammonium citrate 1.2 g Glycyrrhizinic acid 40 g Aminoethylsulfonic acid 80 g Riboflavin sodium phosphate 1.2 g Pyridoxine hydrochloride 10 g Nicotinamide 10 g Citric acid 50 g Sodium citrate 10 g Purified sucrose 2400 g Caramel 60 g Sodium hydroxide Adequate amount Antiseptics Adequate amount Flavor Trace amount Sterile purified water Adequate amount

Example 5 : Sugarcoated tablet

The following ingredients were processed through a regular method to provide mixed particles, and the particle was compressed to form tablets of 240 mg each.

Epinastine hydrochloride 10 g Calcium hydrogen phosphate 250 g Dipotassium glycyrrhizinate 200 g Pyridoxine hydrochloride 50 g Riboflavin butyrate 12 g Lactose 640 g Corn starch 406 g Microcrystalline cellulose 306 g Low substituted hydroxypropylcellulose 130 g Hydroxypropylcellulo se 90 g Light anhydrous silicic acid 45 g Talc 12 g Magnesium stearate 9 g

Subsequently, the tablets were transferred into a coating pan, and coated using coating solution. The equal volume mixture of ethyl alcohol contained 5% weight/volume of hydroxypropylmethylcellulose and purified water to give increase in weight/volume by 10 mg per one tablet. Next, 2% weight/volume of talc, 2% weight/volume of titanium oxide, 3% weight/volume of calcium carbonate, 1% weight/volume of powdered acacia, and aqueous solution containing 60% weight/volume of purified sucrose were used to coat tablets to give increase in weight/volume by 150 mg per one tablet. Finally, aqueous solution containing 60% weight/volume purified sucrose was used to coat tablets to give increase in weight/volume by 30 mg per one tablet. Thus sugarcoated tablets were prepared.

Example 6 : Cream

The following ingredients were processed through a regular method to form a cream of a total weight of 1 kg, added with sodium citrate to adjust at pH 5.

Epinastine hydrochloride 10.0 g Zinc undecylenate 30.0 g Glycyrrhetinic acid 10.0 g Pyridoxine hydrochloride 1.0 g Medium chain fatty acid triglyceride 200.0 g Propylene glycol 150.0 g Glyceryl monostearate 80.0 g Polyoxyethylene cetyl ether 40.0 g Diisopropyl adipate 50.0 g Citric acid 0.1 g Sodium citrate Adequate amount Antiseptics Adequate amount Purified water Adequate amount

Example 7

: Ointment

The following ingredients were processed through a regular method to form an ointment of a total weight of 1 kg. Epinastine hydrochloride 10 g Zinc oxide 100 g Paraffin 40 g Cetanol 30 g White beeswax ^• 30 g Antiseptics Adequate amount White petrolatum Adequate amount

Example 8 : Tablet

The following ingredients were homogeneously mixed. The resulted mixed particles were compressed with a mold to prepare tablets of 250 mg each.

Epinastine hydrochloride 10 g Intin-koo-to extract (Fragrant wormwood flower 2 kg, gardenia 400 g fruit 1.5 kg, rhubarb 0.5 kg) dl-Methylephedrine hydrochloride 90 g Lactose 345 g Microcrystalline cellulose 375 g Light anhydrous silicic acid 5 g Talc 5 g Magnesium stearate 5 g

Example 9 : Powder The following ingredients were homogeneously mixed. The resulted mixed particles were divided into portions of 800 mg to prepare powder compositions.

Epinastine hydrochloride 10 g Powdered bupleurum root 90 g Powdered glehnia root 90 g Powdered poria sclerotium 90 g Powdered cherry bark 90 g Powdered platycodon root 90 g Powdered ginger 90 g Powdered aralia cordata root 90 g Powdered schizonepeta spike 54 g Powdered Glycyrrhiza 54 g Powdered coix seed 54 g Corn starch 648 g Lactose 660 g Magnesium stearate 20 g

Example 10 : Granule

The following ingredients were prepared as granules through a regular method to prepare mixed particles, and packed to give an amount of 1500 mg per one pack for granules.

Epinastine hydrochloride 20 g Glycyrrhiza extract 100 g (Glycyrrhiza 400 g) Thiamine nitrate 30 g Riboflavin 24 g Pyridoxine hydrochloride 90 g Nicotinamide 300 g Calcium pantothenate 60 g Calcium ascorbate 360 g Calcium carboxymethylcellulose 200 g Mannitol 1260 g Corn starch 515 g Aspartame 20 g Acesulfame potassium 20 g Fragrant materials i g Example 11 : Film-coated tablet

The following ingredients were processed through a regular method to provide. mixed particles, and the particle was compressed to form tablets of 200 mg each.

Epinastine hydrochloride 20 g Powdered rhubarb 800 g Powdered smilax rhizome 100 g Powdered forsythia fruit 100 g Powdered ground ivy herb 100 g Lactose 656 g Microcrystalline cellulose 600 g Light anhydrous silicic acid 12 g Talc 6 g Magnesium stearate 6 g

Subsequently, the tablets were transferred into a coating pan, and coated using coating solution. The equal volume mixture of ethyl alcohol contained 5% weight/volume of ) hydroxypropylmethylcellulose and purified water to give increase in weight/volume by 10 mg per one tablet. Thus film-coated tablets were prepared.

Example 12 : Oral solution

Epinastine hydrochloride 4 g Cherry bark fluidextract 800 mL (Cherry bark 800 g) Poria sclerotium fluidextract 120 mL (Poria sclerotium 120 g) Platycodon root fluidextract 240 mL (Platycodon root 240 g) Coix seed fluidextract 240 mL (Coix seed 240 g) Ascorbic acid 40 g Aminoethylsulfonic acid 400 g Citric acid 50 g Sodium citrate 10 g Purified sucrose 2400 g Caramel 60 g Sodium hydroxide Adequate amount Antiseptics Adequate amount Flavor Trace amount Sterile purified water Adequate amount

Example 13 : Ointment

The following ingredients were processed through a regular method to form an ointment of a total weight of 1 kg.

Epinastine hydrochloride 10 g Powdered gardenia fruit 2 g Glycyrrhetinic acid 10 g Crotamiton 20 g Lidocaine 20 g Paraffin 40 g Cetanol 30 g White beeswax 30 g Antiseptics Adequate amount White petrolatum Adequate amount

Claims

1. A pharmaceutical composition for the treatment of skin diseases, comprising a) epinastine or a pharmaceutically acceptable salt thereof and bl) one or more additional pharmaceutically acceptable minerals comprising one or more elements from the group consisting of calcium, zinc, iron, phosphorus, magnesium, potassium, copper, iodine, manganese, selenium, chromium, and molybdenum, or b2) one or more additional pharmaceutically acceptable crude drugs.

2. A pharmaceutical composition according to claim 1 for treatment of skin disease, comprising a) epinastine or a pharmaceutically acceptable salt thereof and bl) one or more additional pharmaceutically acceptable minerals comprising one or more elements from the group consisting of calcium, zinc, iron, phosphorus, magnesium, potassium, copper, iodine, manganese, selenium, chromium, and molybdenum.

3. A pharmaceutical composition according to claim 2, wherein the minerals are selected from the group consisting of calcium gluconate, calcium hydrogen phosphate, dibasic calcium phosphate anhydrous, calcium glycerophosphate, calcium lactate, precipitated calcium carbonate, calcium chloride, calcium carbonate, calcium hydroxide, calcium citrate, calcium L-aspartate, calcium L-glutamate, calcium glycerophosphate, calcium 5'- ribonucleotide, calcium sulfate, tricalcium phosphate, calcium propionate, calcium dihydrogen phosphate (monobasic calcium phosphate), calcium dihydrogen pyrophosphate, carboxymethyl cellulose calcium, calcium stearoyl-2-lactylate, calcium oxide, zinc sulfate, zinc gluconate, zinc undecylenate, zinc oxide, zinc carbonate, zinc chloride, zinc yeast, iron, ferrous sulfate, ferric citrate, sodium ferrous citrate, ferrous gluconate, ferric pyrophosphate (Iron [HI] Pyrophosphate), ferrous succinate, ferric chloride, ferrous lactate, saccharated ferric oxide, chondroitin sulfate/iron colloid, ferric ammonium citrate, iron oxide red (iron sesquioxide), ferritin, heme iron, phosphoric acid, potassium dihydrogen phosphate, potassium monophosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium diphosphate, sodium monophosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, calcium diphosphate, tricalcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, magnesium diphosphate, ammonium diphosphate, ammonium dihydrogen phosphate, diammonium hydrogen phosphate, pentapotassium triphosphate, sodium polyphosphate, sodium hexametaphosphate, tetrapotassium pyrophosphate, disodium dihydrogen pyrophosphate, tetrasodium pyrophosphate, magnesium carbonate, magnesium sulfate, magnesium citrate, magnesium lactate, magnesium chloride, magnesium oxide, magnesium aluminum silicate, magnesium aluminometasilicate, magnesium hydroxide aluminum, magnesium L-aspartate, magnesium L-glutamate, potassium chloride, potassium sulfate, potassium carbonate, potassium dihydrogen citrate, tripotassium citrate, potassium gluconate, potassium acetate, tripotassium phosphate, dipotassium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium hydroxide, aluminum potassium sulfate, potassium L-aspartate, monopotassium L-glutamate, copper sulfate, copper gluconate, sodium copper chlorophyllin, copper yeast, iodine, potassium iodide, sodium iodide, iodolecithine, manganese chloride, manganese sulfate, manganese yeast,sodium selenide, selenium disulfide, selenocysteine, selenomethionine, selenium yeast, chromium chloride, chromium yeast, sodium molybdate, molybdenum yeast.

4. A pharmaceutical composition according to claim 2 or 3, characterized in that the composition is for oral use and the amount of epinastine or a pharmaceutically acceptable salt thereof daily given to an adult lies in the range from 2 to 20 mg in equivalent to epinastine hydrochloride.

5. A pharmaceutical composition according to one or more of the claims 2 to 4, characterized in that the composition is for oral use and the amount of pharmaceutically acceptable minerals lies in the range from 0.3 μg to 4000 mg.

6. A pharmaceutical composition according to one or more of the claims 2 to 5, characterized in that the pharmaceutically acceptable minerals comprises calcium.

7. A pharmaceutical composition according to claim 6, characterized in that the calcium comprising minerals are selected from the group consisting of calcium gluconate, calcium hydrogen phosphate, dibasic calcium phosphate anhydrous, calcium glycerophosphate, calcium lactate and precipitated calcium carbonate.

8. A pharmaceutical composition according to one or more of the claims 2 to 7, characterized in that the amount of calcium given daily to an adult lies in the range from 30 mg to 300 mg.

9. A pharmaceutical composition for oral use according to one or more of the claims 2 to 8, providing for an rapid release of epinastine or a pharmaceutically acceptable salt thereof and a sustained release of all or a part of the one or more minerals.

10. A pharmaceutical composition according to claim 2 or 3, characterized in that the composition is for topical use and the amount of epinastine or a pharmaceutically acceptable salt thereof lies in the range from 1 to 50 mg in equivalent quantity to epinastine hydrochloride per 1 g of the compositions.

11. A pharmaceutical composition according to one or more of the claims 2, 3 or 10 characterized in that the composition is for topical use and the amount of pharmaceutically acceptable minerals lies in the range from 0.1 to 800 mg per lg of the compositions.

12. A pharmaceutical composition according to one or more of the claims 2, 3, 10 or 11, characterized in that the pharmaceutically acceptable minerals comprises zinc.

13. A pharmaceutical composition according to claim 12, characterized in that the zinc comprising minerals are selected from the group consisting of zinc oxide and zinc undecylenate.

14. A pharmaceutical composition according to one or more of the claims 2, 3, 10 to 14, characterized in that the amount of zinc lies in the range from 0.45 mg/g to 450 mg/g of composition.

15. A pharmaceutical pack comprising a pharmaceutical composition comprising epinastine or a pharmaceutically acceptable salt thereof as active agent and a pharmaceutical composition comprising one or more pharmaceutically acceptable minerals comprising one or more elements from the group consisting of calcium, zinc, iron, phosphorus, magnesium, potassium, copper, iodine, manganese, selenium, chromium, and molybdenum as pharmacologically active agent for joined or timely shifted administration.

16. A pharmaceutical pack according to claim 15, wherein the minerals are selected from the group consisting of calcium gluconate, calcium hydrogen phosphate, dibasic calcium phosphate anhydrous, calcium glycerophosphate, calcium lactate, precipitated calcium carbonate, calcium chloride, calcium carbonate, calcium hydroxide, calcium citrate, calcium L-aspartate, calcium L-glutamate, calcium glycerophosphate, calcium 5'- ribonucleotide, calcium sulfate, tricalcium phosphate, calcium propionate, calcium dihydrogen phosphate (monobasic calcium phosphate), calcium dihydrogen pyrophosphate, carboxymethyl cellulose calcium, calcium stearoyl-2-lactylate, calcium oxide, zinc sulfate, zinc gluconate, zinc undecylenate, zinc oxide, zinc carbonate, zinc chloride, zinc yeast, iron, ferrous sulfate, ferric citrate, sodium ferrous citrate, ferrous gluconate, ferric pyrophosphate (Iron [III] Pyrophosphate), ferrous succinate, ferric chloride, ferrous lactate, saccharated ferric oxide, chondroitin sulfate/iron colloid, ferric ammonium citrate, iron oxide red (iron sesquioxide), ferritin, heme iron, phosphoric acid, potassium dihydrogen phosphate, potassium monophosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium diphosphate, sodium monophosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, calcium diphosphate, tricalcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, magnesium diphosphate, ammonium diphosphate, ammonium dihydrogen phosphate, diammonium hydrogen phosphate, pentapotassium triphosphate, sodium polyphosphate, sodium hexametaphosphate, tetrapotassium pyrophosphate, disodium dihydrogen pyrophosphate, tetrasodium pyrophosphate, magnesium carbonate, magnesium sulfate, magnesium citrate, magnesium lactate, magnesium chloride, magnesium oxide, magnesium aluminum silicate, magnesium aluminometasilicate, magnesium hydroxide aluminum, magnesium L-aspartate, magnesium L-glutamate, potassium chloride, potassium sulfate, potassium carbonate, potassium dihydrogen citrate, tripotassium citrate, potassium gluconate, potassium acetate, tripotassium phosphate, dipotassium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium hydroxide, aluminum potassium sulfate, potassium L-aspartate, monopotassium L-glutamate, copper sulfate, copper gluconate, sodium copper chlorophyllin, copper yeast, iodine, potassium iodide, sodium iodide, iodolecithine, manganese chloride, manganese sulfate, manganese yeast,sodium selenide, selenium disulfide, selenocysteine, selenomethionine, selenium yeast, chromium chloride, chromium yeast, sodium molybdate, molybdenum yeast.

17. Use of a pharmaceutical composition or pack according any of the preceding claims for the manufacture of a medicament for the treatment and/or prevention of skin diseases,

18. Use according to claim 17 wherein the skin disease are related to allergic reactions.

19. Use according to claim 17 or 18 wherein the skin disease is urticaria, eczema, skin irritation, dermatitis, pruritus, prurigo and psoriasis vulgaris.

20. A pharmaceutical composition according to claim 1, for treatment of skin disease, comprising a) epinastine or a pharmaceutically acceptable salt thereof and b2) one or more additional pharmaceutically acceptable crude drugs.

21. A pharmaceutical composition according to claim 20, wherein the pharmaceutically acceptable crude drugs are selected from the group consisting of fragrant wormwood flower, gardenia fruit, rhubarb, bupleurum root, glehnia root, poria sclerotium, cherry bark, platycodon root, ginger, aralia cordata root, schizonepeta spike, glycyrrhiza, coix seed, smilax rhizome, forsythia fruit, ground ivy herb, magnolia flower, and/or cnidium rhizome.

22. A pharmaceutical composition according to claim 20 or 21, characterized in that the composition is for oral use and the amount of epinastine or a pharmaceutically acceptable salt thereof daily given to an adult lies in the range from 2 to 20 mg in equivalent to epinastine hydrochloride.

23. A pharmaceutical composition according to one or more of the claims 20 to 22, characterized in that the composition is for oral use and the daily dose of the crude drugs lies in the range from 5 mg to 30000 mg of crude drug substance.

24. A pharmaceutical composition for oral use according to one or more of the claims 20 to 23, providing for a rapid release of epinastine or a pharmaceutically acceptable salt thereof and a sustained release of all or a part of the one or more crude drags.

5 25. A pharmaceutical composition according to claim 20 or 21, characterized in that the composition is for topical use and the amount of epinastine or a pharmaceutically acceptable salt thereof lies in the range from 1 to 50 mg in equivalent quantity to epinastine hydrochloride per 1 g of the compositions.

26. A pharmaceutical composition for treatment of skin disease according to one or more of 10 the claims 20, 21 and 25 characterized in that the composition is fo>r topical use and the amount of crude drugs lies in the range from 0.1 to 800 mg of crude drug substance per lg of the composition.

27. A pharmaceutical pack comprising a pharmaceutical composition comprising epinastine or a pharmaceutically acceptable salt thereof as active agent and a pharmaceutical

15 composition comprising one or more pharmaceutically acceptable crude drugs as pharmacologically active agent for joined or timely shifted administration.

28. A pharmaceutical pack according to claim 27 wherein the crude drugs are selected from the group consisting of fragrant wormwood flower, gardenia fruit, πrhubarb, bupleurum root, glehnia root, poria sclerotium, cherry bark, platycodon root, ginger, aralia cordata

20 root, schizonepeta spike, glycyrrhiza, coix seed, smilax rhizome, forsythia fruit, ground ivy herb, magnolia flower, and/or cnidium rhizome.

29. Use of a pharmaceutical composition or pack according one or more of the claims 20 to 28 for the manufacture of a medicament for the treatment and/or prevention of skin diseases.

25 30. Use according to claim 29 wherein the skin disease are related to aHlergic reactions.

31. Use according to claim 29 or 30 wherein the skin disease is urticaria, eczema, skin irritation, dermatitis, pruritus, prurigo and psoriasis vulgaris.