WO2008148572A1

WO2008148572A1 - Anti-inflammatory active ingredient combination for the treatment of diseases of the skin and mucous membranes

Info

Publication number: WO2008148572A1
Application number: PCT/EP2008/004566
Authority: WO
Inventors: Marianne Petersen-Braun; Sabine Rabini; Sabine GLÄSER; Klaus Kluthe
Original assignee: Bayer Consumer Care Ag
Priority date: 2007-06-08
Filing date: 2008-06-07
Publication date: 2008-12-11
Also published as: DE112008001135A5

Abstract

The invention relates to combinations comprising at least one anti-inflammatory active ingredient and at least one anti-allergic active ingredient, and/or at least one active ingredient selected from the group comprising pantothenic acid and pantothenic acid derivatives, for the treatment of diseases and symptoms of diseases of the skin and mucous membranes, particularly of allergic diseases and symptoms. The invention further relates to pharmaceuticals containing them, and to the production thereof.

Description

Anti-inflammatory drug combinations for the treatment of diseases of the skin and mucous membranes

The invention relates to combinations comprising at least one anti-inflammatory agent and at least one antiallergic agent and / or at least one selected from the pantothenic acid and pantothenic acid group selected active ingredient for the treatment of diseases and disease symptoms of the skin and mucous membranes, in particular allergic diseases and symptoms, drugs containing them and its production.

The available for an anti-allergic therapy drugs are generally symptomatic, since a causal therapy could be effected only by complete antigenic deficiency. In the symptomatic treatment of allergic diseases mainly drugs from the drug class of antihistamines and from the class of corticosteroids are used.

In the development of allergic reactions and the symptoms that occur, the release of mediators (eg histamine) by mast cells and basophilic granulocytes plays a central role. The released mediators cause increased permeability of vessels, spastic contractions of the smooth muscle, and - by activation of other cell types of the immune system - local inflammatory reactions. Antihistamines prevent the occurrence or effects of mediators of allergic reactions (prostaglandins, especially PGD2, and histamine) and have an antagonistic effect on the migration of eosinophilic granulocytes in atopic patients. Furthermore, the allergic reaction can be counteracted by administration of anti-inflammatory and immunosuppressive corticosteroids (glucocorticoids). Based on this, the use of these drug classes in the symptomatic therapy of allergic diseases.

The symptoms caused by allergic reactions mainly affect the skin, the mucous membranes, especially the mucous membranes of the respiratory tract (nasal cavity, paranasal sinuses, oral cavity, pharynx, larynx, trachea, bronchi, bronchioles), the bronchi, the gastrointestinal tract, the conjunctiva of the eye as well as the vascular system.

Common symptoms or clinical manifestations of allergic diseases are e.g. The following: skin itching, redness, eczema, rashes, urticaria, purpura; Edema in the mucous membrane, swelling of the mucous membrane, secretion from mucous membranes, allergic Rhinitis, allergic bronchial asthma, allergic alveolitis, as well as allergic conjunctivitis.

Antihistamines and glucocorticoids are approved as both oral (i.e., systemic) and topical drugs for the treatment of allergic symptoms. However, the therapeutic efficacy of the known antihistamines and glucocorticoids is often inadequate and an increase in dosage is not justifiable due to the associated risk of side effects. Often it comes with the symptomatic anti-allergic therapy

Use of drugs from the classes of antihistamines and glucocorticoids to undesirable side effects such. As skin dryness, skin atrophy, susceptibility of the skin or mucous membrane for fungal infections and bacterial and viral infections.

Furthermore, in the symptomatic therapy of allergic diseases, agents from the class of mast cell degranulation inhibitors and from the class of leukotriene receptor antagonists are used. Furthermore, it is known from WO 01/19330 A1 that inhibition of the release of mediators from mast cells is effected by pantothenic acid and its derivatives (eg dexpanthenol), but also by the amino acid glycine, and thereby the allergic reaction can be alleviated.

Usually, dexpanthenol is used as a component in topical medicines. For example, EP 1 159958 A1 describes a nasal ointment containing dexpanthenol as a nourishing ingredient. DE 10005936 A1 discloses a cream for external use in the nose area, which contains a combination of allantoin and dexpanthenol. DE 19541919 A1 describes a pharmaceutical preparation for the treatment of acute rhinitis which comprises a sympathomimetic with 2-imidazoline structure (eg oxymetazoline) suitable for topical use in combination with a pantothenol derivative, e.g. As dexpanthenol contains. The combination with dexpanthenol alleviated the side effects caused by the sympathomimetic.

The object underlying the present invention was to provide medicaments for the therapeutic treatment of diseases and disease symptoms of the skin and mucous membranes, in particular of allergic diseases and symptoms of the skin or the mucous membranes, which have improved efficacy and / or a lower side-effect potential.

According to the present invention, this object is achieved by a combination comprising at least one antiinflammatory active ingredient and additionally at least one antiallergic active ingredient or / and at least one of the pantothenic acid and pantothenic acid derivatives Surprisingly, it has been found that by the combined administration of an anti-inflammatory drug and an anti-allergic drug or by the combined administration of an anti-inflammatory drug and a group comprising pantothenic acid and pantothenic acid derivatives, an increase in therapeutic efficacy and an accelerated course of cure with a rapid response This can lead to an unexpected and synergistic enhancement of the anti-inflammatory and / or anti-allergic effects, based on the efficacy of the respective monopraparates

This makes it possible to reduce the dose of the antiallergic or the antiinflammatoπschen drug in comparison to conventional medicaments for the symptomatic treatment of allergy, which does not contain the drug combination according to the invention was also surprisingly found - compared to the above-mentioned conventional drugs - reduction of side effects The inventive Combinations are useful m for the treatment of allergic symptoms or diseases of the skin, mucous membranes, especially the respiratory tract and especially the nose, or the conjunctiva. The active compound combinations according to the invention are also suitable for the treatment of other dermatological diseases, in particular for the treatment of inflammatory skin diseases

The inventive combinations are also advantageous because they have a reduced side effect potential The occurrence of side effects such as skin dryness can be significantly reduced by means of the inventive drugs due to the use of said drug combinations This is particularly important because some antiallergic agents themselves in topical application Additional advantages result with the medicaments according to invention in that due to the content of antiinflammatoπschen active substances or to Pantothensaure or Pantothensauredπvaten a favorable influencing of the Entzundungssymptome, like redness, swelling and heat development, Dry or burning mucous membranes, or crusting allows

In the context of the present invention, the term "antnnflammatoπsch" is considered to be synonymous with the term "antiphlogistic" Furthermore, the term "substance or" active ingredient refers both to individual, chemically defined compounds as well as mixtures, natural products or natural product mixtures According to a preferred embodiment of the invention, the active ingredient combination comprises at least one anti-inflammatory agent selected from the group consisting of sulphonated shale oils, bituminosulphonates, in particular ammonium bituminosulphonate or bituminous sulphonate, as well as coal tar, coal tar extracts and other tars. The active ingredients of the abovementioned group are preferably used in medicaments for external application on the skin.

The above-mentioned substances are preferably used in a proportion of 0.1 to 70 wt .-%, in particular from 5 to 50 wt .-%, in each case based on the respective drug.

According to a further preferred embodiment of the invention, the active ingredient combination comprises at least one anti-inflammatory substance which is of vegetable origin. This may be a single substance, a mixture of substances, a liquid or solid or dry extract, a distillate or an oil. Particular preference is given to herbal substances which are borage (Borago officinalis), evening primrose (Oenothera biennis), witch hazel, common sunflower (Echinacea angustifolia), chamomile (Chamomilla recucita, C. nobile, Matricaria matricarioides), arnica (Arnica chamissonis, A. montana). , Calendula (Calendula officinalis), thyme (Thymus spp.), Aloe vera, sage (Salvia officinalis), mint (Mentha spp.), St. John's wort (Hypericum perforatum), rosemary (Rosmarinus officinalis), sea-buckthorn (Hippophae rhamnoides), Cardiospermum halicacabum , Myrrh (Commiphora spp.), Ratanhia, Fennel (Foeniculum vulgare), Willow (Salix spp.), Yarrow (Achillea millefolium), Coltsfoot (Tussilago farfara), Comfrey (Symphytum officinale), Devil's Claw (Harpagophytum procumbens), Bittersweet (Solanum dulcamara), Elderberry (Sambucus nigra), Eucalyptus, Tea tree (Melaleuca altemifolia), Tea bush (Camellia sinensis), Licorice (Glycyrrhiza spp.), Melissa (Melissa officinalis), Coriander, Centaury (Centauri stinging nettle (Urtica spp.), pineapple, spruce, pine or oak. In order to obtain the herbal active ingredients, in particular the leaves, roots, flowers, fruits or bark of the plants are used. The respective suitable plant species, plant parts and extraction methods are known to the person skilled in the art.

As herbal substances with anti-inflammatory effect are in particular tannins, essential oils, Azulene, Proazulene, bisabolols, bisabololides, flavonoids, flavones, anthocyanins, triterpenes, monoterpene alcohols, phenolcarboxylic acids, polyphenols, unsaturated fatty acids, hypericin, carotenoids, allantoin, bromelain, glycyrrhizin, glycyrrhizic acid or Salts of Glycyrrhizinsäure, as well as combinations of the aforementioned substances into consideration. In addition to tannins or tannin extracts of plant origin and synthetic tanning agents can be used, for. As phenol-methanal-urea-polycondensates. Furthermore come as herbal substances with anti-inflammatory effect, in particular evening primrose oil and borage oil and other vegetable oils with anti-inflammatory effect, such as. As wheat germ oil, into consideration.

The proportion of plant anti-inflammatory substances is preferably 0.05 to 75% by weight, preferably 0.1 to 50% by weight, depending on the nature of the active ingredients, the particular dosage form used and the nature of the therapeutic use to the respective drug.

According to a further preferred embodiment, the combination according to the invention comprises at least one anti-inflammatory active ingredient selected from the group consisting of vitamin A, carotenes, carotenoids, tretinoin (all-trans-retinoic acid), tocopherols (vitamin E) and biotin. These active ingredients are preferably used in a proportion of 0.01 to 20 wt .-%, in particular from 0.05 to 5 wt .-%, based on the respective drug.

The invention includes both active ingredient combinations containing only a single anti-inflammatory drug from said drug groups, as well as drug combinations containing two or more anti-inflammatory drugs, each selected from one or more of the aforementioned groups.

The group of pantothenic acid derivatives includes in particular dexpanthenol, DL-panthenol, salts of pantothenic acid (eg Na-pantothenate, Ca-pantothenate), esters of pantothenic acid (eg ethyl, methyl ester), panthenol-ether (e.g. Ethyl or methyl ether), panthenol thioether and panthenyl triacetate. Dexpanthenol (= D - (+) - pantothenyl alcohol) is most preferred.

The relative proportion of dexpanthenol (or of the pantothenic acid derivative and / or pantothenic acid) can be varied within wide limits, depending on the respective desired effects. Preferably, the dexpanthenol content is 0.1 to 95 wt .-%, in particular 0.5 to 50 wt .-%, particularly preferably 0.5 to 30 wt .-%, each based on the total amount of active ingredient.

Particularly suitable antiallergic agents are active substances selected from the group consisting of antihistamines, corticosteroids, synthetic mast cell degranulation inhibitors and leukotriene receptor antagonists. Particularly preferred are drugs from the drug class of antihistamines and from the drug class of corticosteroids used. The corticosteroids used according to the invention are generally glucocorticoids. Antihistamines (histamine HI receptor antagonists, histamine H2 receptor antagonists) which are suitable for a therapeutic treatment of allergic symptoms of the skin or mucous membranes and are therefore suitable for use in the combination of active substances according to the invention are known in principle to the person skilled in the art. Antihistamines are substances that antagonize the action of the released histamine on the Hl receptor (or the H2 receptor), thereby eliminating the effect of histamine on Hl receptors, especially on the peripheral vessels. Particularly suitable antihistamines in connection with the present invention are the following active substances: ketotifen, thonzylamine, mepyramine, thenalidine, triphenylamine, chloropyramine, promethazine, tolpropamine, dimetindene, clemastine, bamipine, loratadine, isothipendyl, diphenhydramine, diphenhydramine methyl bromide, chlorphenoxamine, pheniramine, Diphenylpyraline, dioxopromethazine, dimenhydrinate, thiethylperazine and meclocine, azelastine, levocabastine, astemizole, mebhydroline, terfenadine, mequitazine, cetirizine, emedastine, mizolastine, olopatadine, epinastine and antazoline. Particularly preferred antihistamines are: bamipin, clemastine, chlorphenoxamine, azelastine, terfenadine, loratadine.

The relative proportion of the antihistamine (or antihistamines) is determined in a manner known to those skilled in the art, depending on the pharmacological properties and the nature of the particular dosage form used.

As corticosteroids are basically all glucocorticoid drugs into consideration, whose therapeutic efficacy in the treatment of allergic diseases or symptoms is known. In particular, in the context of the present invention, the following active ingredients are contemplated: triamcinolone, dexamethasone, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone buteprate, prednisolone, betamethasone, methylprednisolone, clobetasone, flumetasone, fluocortin, fluperolone, fluorometholone, flupredniden, desonide, triamcinolone, alclometasone , dexamethasone, clocortolone, betamethasone, Fluclorolon, desoximetasone, fluocinolone, fluocortolone, diflucortolone, fludroxycortide, fluocinonide, budesonide, diflorasone, amcinonide, halometasone, mometasone, methylprednisolone, beclomethasone, hydrocortisone aceponate, fluticasone, prednicarbate, difluprednate, Ulobetasol, clobetasol, halcinonide, medrysone , Desonide, formocortal, rimexolone, mazipredon, flunisolide and tixocortol. Particularly preferred corticosteroids are: hydrocortisone, beclomethasone dipropionate, dexamethasone.

The invention further includes embodiments which provide that the drug combination comprises at least one synthetic antiallergic drug not selected from the group consisting of antihistamines and corticosteroids. Come here in particular, drugs from the group comprising synthetic mast cell degranulation inhibitors and leukotriene receptor antagonists into consideration.

Mast cell degranulation inhibitors, also referred to as mast cell stabilizers, are substances that inhibit the release of histamine from mast cells. Exemplary and preferred representatives of this class of drugs are cromoglycic acid, spaglumic acid, nedocromil and lodoxamide.

Leukotriene receptor antagonists are substances that inhibit leukotriene synthesis and / or leukotriene effects. Leukotrienes are involved in the development and chronicity of allergic inflammatory symptoms. Exemplary and preferred representatives of this class of drugs are montelukast, pranlukast, ibudilast and zafirlukast.

The invention encompasses both active ingredient combinations containing only a single antiallergic active ingredient - selected from one of the abovementioned groups - as well as active ingredient combinations which contain two or more antiallergic active ingredients, each selected from one or more of the abovementioned groups.

The proportion of the antiallergic agent is preferably in the range from 0.01 to 25% by weight, in particular from 0.05 to 10% by weight, based in each case on the total amount of active ingredient.

The active ingredients exemplified in the preceding paragraphs are not a complete and exhaustive list of active ingredients from the classes of herbal anti-inflammatory drugs, antihistamines, glucocorticoids, synthetic mast cell degranulation inhibitors and leukotriene receptor antagonists. The mention of these substances is only illustrative of these drug classes. Of course, other active ingredients from the mentioned classes of active substances can be used in the context of the invention. In addition, the active substances according to the invention can also be used in the form of their pharmaceutically acceptable salts.

Pharmaceutically acceptable salts of the compounds of the invention may be acid addition salts of the compounds with mineral acids, carboxylic acids or sulfonic acids. Particular preference is given, for example, to salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid, oxalic acid, succinic acid, butyric acid, decanoic acid, aspartic acid or benzoic acid. - o -

However, salts with customary bases can also be mentioned as salts, for example alkali metal salts (for example sodium or potassium salts), alkaline earth salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, Dibenzylamine, N-methylmorpholine, dihydroabiethylamine, 1 -phenamine or methyl-piperidine.

The active substance combination according to the invention preferably comprises a) at least one anti-inflammatory substance selected from the group consisting of sulphonated shale oils, bituminous sulphonates, coal tar extracts and other tars, and at least one antiallergic active substance, or b) at least one herbal substance having an antiinflammatory effect and at least one or (c) at least one anti-inflammatory agent selected from the group consisting of sulfonated shale oils, bituminosulfonates, coal tar, coal tar extracts and other tars, at least one anti-inflammatory agent, and at least one antiallergic agent, or d) at least one anti-inflammatory agent A fabric selected from the group consisting of sulfonated shale oils, bituminous sulfonates, coal tar, coal tar extracts and other tars, and at least one of the Pan or e) at least one herbal substance having an antiinflammatory effect and at least one active substance selected from the pantothenic acid and pantothenic acid derivatives group; or f) at least one antiinflammatory substance selected from sulphonated shale oils, bituminosulphonates, coal tar, coal tar extracts and other tars

G) at least one herbal substance having an antiinflammatory effect, at least one antiallergic active substance, and at least one active substance selected from the group comprising pantothenic acid and pantothenic acid derivatives, or at least one active substance selected from the group consisting of pantothenic acid and pantothenic acid derivatives; or h) at least one anti-inflammatory agent selected from the group consisting of sulfonated shale oils, bituminosulfonates, coal tar, coal tar extracts and other tars, at least one anti-inflammatory agent, at least one anti-allergic agent, and at least one of pantothenic acid and pantothenic acid derivatives Group selected drug.

In the simplest case, an active ingredient combination (a) to (h) consists exclusively of the active ingredient components listed above. Optionally, those described above Active ingredient combinations contain at least one other active ingredient, which is not selected from the above-mentioned active ingredient groups. Said further active ingredient may preferably be selected from the group comprising dermatics (eg urea, heparin, hyaluronic acid, glycine, lactic acid and its salts, pyroglutamic acid, salicylic acid, dimethyl fumarate and ethyl hydrogen fumarate), antibiotics (eg sulphonamides, erythromycin ), Antiseptics (eg chlorhexidine), local anesthetics (eg lidocaine, polidocanol), decongestants (eg sympathomimetics such as xylometazoline) as well as skin care substances (eg jojoba oil, lanolin, vegetable oils and fats ) and sunscreen substances (UV-A filter, UV-B filter, broadband filter).

The proportion of the said further active ingredient (s) can be chosen freely, this proportion is preferably 0.05 to 50 wt .-%, in particular 0.1 to 20 wt .-%, each based on the drug.

According to a preferred embodiment of the invention, it is provided that the active ingredient combination additionally contains glycine. The additional administration of glycine can achieve a further increase in therapeutic efficacy. Preferably, glycine is present in a proportion of 0.1 to 25 wt .-%, in particular 0.5 to 10 wt .-%, in each case based on the total active ingredient content, in the active ingredient combination.

"Combination" within the meaning of the invention is understood to mean not only administration forms which contain all components in a common administration form (so-called fixed combinations), and combination packages which contain the components separated from one another in a single package ("kit") but also simultaneously or staggered components, if used to treat the same disease / symptom.

The active substances of the medicaments and pharmaceutical formulations according to the invention are particularly suitable for being formulated in a fixed combination. It is known that the application reliability (compliance) in patients depends crucially on the factors number of dosage forms per application time, and optionally on the size and weight of the (solid peroral) dosage form. Therefore, both the number of different medicines to be taken separately should be as small as possible (the advantage of a fixed combination) and, if necessary, the size and weight of a solid oral dosage form should be kept as small as possible without compromising therapeutic potency. This makes the application as comfortable as possible for the patient. By implementing fixed combinations, the highest possible patient compliance is provided and the safety and reliability of the therapy are decisively improved. The medicaments according to the invention preferably contain the active ingredient combination according to the invention in the form of a "fixed combination"; This means that all active ingredients which form the respective active ingredient combination are present together in a dosage form and administered together.

For therapeutic use, the active compound combinations according to the invention in the form of medicaments are generally administered locally (i.e., topically) to those areas of the skin or mucous membrane which are affected by allergic symptoms.

The medicaments according to the invention are preferably formulated as solid, semi-solid, liquid or gaseous dosage forms for topical application to the skin or mucous membrane, in particular as powder, powder, plaster, dust aerosol, granules, lozenge, lozenge, chewing gum, gel, ointment, lotion, paste, Shampoo, emulsion, suspension, solution, gargle, juice, syrup, oil, aerosol or inhalant.

For the treatment of allergic symptoms on or in the eye, the following dosage forms are particularly suitable: eye ointments, eye sprays, eye tablets, eye drops, eye lotions, eye baths, eye salves.

For the treatment of allergic symptoms of the nose or paranasal sinuses in particular the following dosage forms are considered: nose drops, nasal sprays, nose creams, creams, lozenges, suspensions or solutions, tinctures, lotions, emulsions, nose powder, powders, gels, nasal douche, nasal irrigation, aerosols, inhalants. The invention also includes dosage forms for the external treatment of the nose (eg, ointments, gels, creams).

For the treatment of allergic symptoms of the pharynx or lower respiratory tract (trachea, bronchi, bronchioles, alveoli), the following dosage forms are particularly suitable: aerosol, inhalant (suspensions, solutions), throat spray, oral spray, powder for inhalation, drops, tablets, lozenges, Pastilles, capsules, syrups, tinctures, gargles.

For the treatment of allergic symptoms of the skin or mucous membranes, especially the following dosage forms are considered: gels, ointments, solutions, powders, creams, sprays, emulsions, suspensions, tinctures, lotions. The abovementioned solid, semisolid, liquid or gaseous dosage forms are known in principle to the person skilled in the art and are described in the literature; the same applies with regard to the preparation of such dosage forms and the pharmaceutically acceptable auxiliaries suitable therefor. The preparation of the medicaments according to the invention can take place taking into account the active compound combinations to be used according to the invention with the methods known for the respective dosage form using pharmaceutical excipients, as are familiar to the person skilled in the art.

Suitable adjuvants are, for example: particulate carriers (eg talc, zinc oxide, starch, starch derivatives, diatomaceous earth); gel-forming substances (eg gelatin, tragacanth, cellulose derivatives, alginates, polyacrylic acid); Humectants (eg, urea, glycerol, propylene glycol), pressure-sensitive adhesives (eg, polyacrylates, as well as tackifier resins); Ointment bases (eg vaseline, fats, cellulose derivatives, polyacrylic acid, polyethylene glycols); Emulsifiers (eg wool wax, sorbitan esters, monoglycerides); Preservatives (e.g., benzalkonium chloride), antioxidants (e.g., butylhydroxyanisole), thickening agents (e.g., hydroxypropylmethylcellulose), pH corrigents; Binders (eg polyvinylpyrrolidone, starch, hydroxypropylmethylcellulose, polyethylene glycols), fillers (eg microcrystalline cellulose, sorbitol), dyes, flavorings, sweeteners (eg sorbitol, aspartame); Solvents (eg, water, ethanol, ethanol-water mixtures); Solubilizers (eg, glycerol, propylene glycol); Skin penetration enhancers (eg, propylene glycol); Plasticizers (eg, sorbitol, glycerin, phthalic acid esters); Wetting agents (e.g., sodium lauryl sulfate, polysorbates); synthetic and natural oils (eg medium chain triglycerides); Propellants for inhaled dosage forms (eg norflurane, cryoflurane, dichlorofluoromethane, trichlorofluoromethane, propane, butane, isobutane, nitrogen).

Liquid dosage forms are also prepared by standard methods with pharmaceutically acceptable excipients and either contain the active ingredients dissolved or suspended. Typical application volumes of these pharmaceutical preparations are between 1 and 10 ml. Examples of auxiliaries in these liquid formulations are: solvents (eg water, alcohol, natural and synthetic oils such as medium-chain triglycerides), solubilizers (eg glycerol, glycol derivatives), wetting agents (eg polysorbate, sodium lauryl sulfate ), as well as other auxiliaries, which are needed for the preparation of pharmaceutical formulations of the desired properties, eg viscosifiers, pH corrigents, sweeteners and flavors, antioxidants, stabilizers and / or preservatives.

Furthermore, according to further embodiments of the invention, dosage forms may be used which enable a delayed or controlled release of active ingredient. Drug forms with controlled or prolonged release of active ingredient (eg depot preparations and sustained-release preparations, as well as therapeutic systems) are generally known to the person skilled in the art. By modifying the composition of the drugs by known means, for example by means of coatings, embedding or microencapsulation, drug release from the drug can be controlled. The delayed or controlled release may optionally affect only one, several or all active ingredient components of the fixed drug combination.

The total active ingredient content in the medicaments according to the invention is preferably in the range from 0.05 to 70% by weight, in particular in the range from 0.1 to 50% by weight, particularly preferably in the range from 0.5 to 15% by weight. , in each case based on the total weight of a drug. The active substances can be present in the medicaments in particular in particulate, dispersed, dissolved, suspended or emulsified form.

Optionally, it may be necessary to deviate from the stated amounts, depending on the body weight or the type of application route, the individual behavior towards the drugs, the nature of their formulation and the time or interval at which the administration takes place. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The medicaments according to the invention are preferably medicaments for intranasal, intraocular or dermal application, or medicaments for inhalation administration for the treatment of the respiratory tract (in particular the bronchi), or medicaments for local application in the oral and / or pharyngeal area. As a result, the medicaments according to the invention are particularly suitable for the treatment of allergic symptoms of the nasal mucosa, the conjunctiva, the skin, the oral mucosa, the mucosa of the pharynx, or the lower respiratory tract (eg trachea, bronchi, bronchioles).

The invention further extends to the use of a combination of active substances as defined above for the treatment of diseases and disease symptoms of the skin, mucosa (especially mucous membranes of the respiratory tract) or conjunctiva, as well as to the use of such an active ingredient combination for the manufacture of a medicament for the treatment of said allergic symptoms. The term "treatment" includes preventive (prophylactic) treatment.

The above-mentioned allergic symptoms are, in particular, those occurring in the following allergic diseases: atopic eczema, psoriasis, contact dermatitis, Allergic rhinitis, allergic rhinoconjunctivitis, allergic conjunctivitis, allergic sinusitis Insect bites, drug allergy, drug eruption.

The aforementioned allergic symptoms include in particular the following: itching; Redness;

erythema; eczema; Scaling of the skin; Crusting; Oozing the skin; Dry skin;

Dermatitis; Wheals, papules, pustules, puffiness; mucosal atrophy; Inflammatory conditions of a mucous membrane, especially the nasal mucosa; Burning in the nasopharynx, coughing, coughing; Sore throat, scratching, dryness in the throat;

Hyperaemia, edema, hypertrophy or swelling of a mucous membrane, especially the

nasal mucous membrane; increased secretion of secretions (serous, mucous) of a mucous membrane, especially the nasal mucosa; Sneezing, sneezing attacks; Obstruction of nasal breathing; Redness and swelling of the conjunctiva of the eye, growths of the conjunctiva; Eyelid edema, lids.

Furthermore, the active ingredient combinations and medicaments according to the invention can be used for the treatment of diseases of the skin and the subcutaneous tissue, in particular for the treatment of the following skin diseases: infections of the skin or subcutis caused by bacteria, fungi or viruses, in particular impetigo, abscesses, boils, Carbuncle; bullous dermatoses, in particular pemphigoid diseases; non-allergic dermatitis; loan; pruritus; decubitus; lupus; Leg Ulcer.

The invention further includes a method for the therapeutic treatment of a person suffering from a disease of the skin or the subcutaneous tissue, or the one or more allergic

Symptoms on the skin, mucosa (especially mucous membranes of the nose and respiratory tract) or conjunctiva, and requires therapeutic treatment. Such a therapeutic method of the invention comprises administering a fixed one

Active substance combination, as defined above, in a therapeutically effective dose. If necessary, the administration of the drug combination is repeated at appropriate intervals to achieve the desired therapeutic effect.

The administration of the drug combination is preferably carried out by means of a solid, semi-solid, liquid or gaseous dosage form, as mentioned above. The active ingredient combination, or a drug containing such a combination, is generally applied topically, ie to those areas of the skin or mucous membrane affected by allergic symptoms. Preferably, the drug or drug combination is applied to the skin, to a mucous membrane, orally, intranasally, intratracheally, intrabronchially or intraocularly. The particular suitable therapeutic dose depends on the nature of the active ingredients contained in the respective drug combination and the nature of the symptoms to be treated, and can be determined in a manner known to those skilled in the art. The medicaments according to the invention may contain the active substances mentioned in the usual dosages. Due to the mentioned synergistic effect, the dosage of each active ingredient of the active ingredient combination contained in the medicaments according to the invention can be chosen lower than the dosage which is customary for a single preparation of the respective active ingredient.

The active compound combinations and medicaments according to the invention can be used not only in the field of human medicine but also in the field of veterinary medicine for the treatment of allergic symptoms of the skin or mucous membrane.

The invention will be explained in more detail with reference to the formulations given in the following examples:

Example 1: ointment

10% by weight coal tar

5% by weight of dexpanthenol

in an ointment base (white vaseline, wool wax, medium-chain triglycerides).

The ointment can be used for the treatment of eczema, especially allergic eczema, as well as for

Treatment of psoriasis vulgaris be used. The ointment is applied thinly one to three times daily to the affected skin.

Example 2: ointment

10% by weight of coal tar 5% by weight of dexpanthenol 5% by weight of zinc oxide

in an ointment base (white vaseline, castor oil, propylene glycol).

The ointment can be used to treat eczema, especially allergic eczema. The ointment is applied thinly one to three times daily to the affected skin.

Example 3: Hydrogel

10% by weight coal tar solution 0.05% by weight of clemastine hydrogen fumarate

in a hydrogel (glycerol, hydroxypropylcellulose, isopropanol, propylene glycol). The hydrogel is used to treat itchy skin diseases, especially allergic skin diseases. The gel is applied thinly several times daily to the affected skin.

Example 4: Cream

5% by weight ammonium bituminosulfonate 0.1% by weight betamethasone 17 valerate

in a lipophilic cream (white vaseline, wool wax, wool wax alcohols, sorbitan fatty acid esters, purified water). The cream is used to treat eczema, dermatitis and inflammatory dermatoses. The cream is applied one to several times a day thinly on the affected skin.

Example 5: ointment

2% by weight of chamomile extract 5% by weight of dexpanthenol

in an ointment base (wool wax, wool wax alcohols, medium chain triglycerides, white vaseline, purified water). The ointment is used to treat skin and mucous membrane inflammation.

Example 6: ointment

2% by weight of chamomile extract

5% by weight of dexpanthenol

2% by weight allantoin

in an ointment base (wool wax, wool wax alcohols, medium chain triglycerides, white vaseline, purified water). The ointment is used to treat inflammatory skin diseases.

Example 7: Ointment 2 wt .-% chamomile extract l, 5 wt .-% chlorophenoxamine-HCl 5 wt .-% dexpanthenol

in an ointment base (wool wax, wool wax alcohols, medium chain triglycerides, white vaseline, propylene glycol, purified water). The ointment is used to treat allergic and / or inflammatory skin diseases.

Example 8: Nasal Spray

10% by weight chamomile flower fluid extract 0.1% by weight azelastine HCl

Excipients: purified water, benzalkonium chloride, disodium EDTA.

The spray volume is 0.14 ml, corresponding to a single dose of 0.14 mg azelastine HCl per spray.

The nasal spray is used to treat allergic rhinitis. For application, one spray is injected into each nostril one to three times a day.

Example 9: Nasal Spray

10% by weight of chamomile flower fluid extract 2% by weight of dexpanthenol

Excipients: purified water, benzalkonium chloride, disodium EDTA.

The spray volume is 0.14 ml, corresponding to a single dose of 0.14 mg azelastine HCl per spray. The nasal spray is used to treat allergic rhinitis and other inflammatory diseases of the nasal mucosa and paranasal sinuses. For application one to several times a day a spray is sprayed into each nostril.

Example 10: Nasal Spray

10% by weight of chamomile flower extract 3.1% by weight of cromoglicinic acid, disodium salt 5% by weight of dexpanthenol Excipients: purified water, benzalkonium chloride,

Disodium EDTA.

The spray volume is 0.09 ml, corresponding to a single dose of 2.8 mg

Cromolynic acid per spray.

The nasal spray is used to treat allergic rhinitis. For application, one spray is injected into each nostril one to five times a day.

Claims

claims

A combination comprising at least one anti-inflammatory drug and at least one antiallergic drug or / and at least one drug selected from the group consisting of pantothenic acid and pantothenic acid derivatives.

A combination according to claim 1, characterized in that it contains at least one anti-inflammatory substance selected from the group consisting of sulphonated shale oils, bituminous sulphonates, coal tar, coal tar extracts, and other tars.

3. Combination according to claim 1 or 2, characterized in that it contains at least one vegetable anti-inflammatory substance.

4. A combination according to claim 1, characterized in that the combination comprises a) at least one anti-inflammatory substance selected from the group consisting of sulfonated shale oils, bituminosulfonates, coal tar, coal tar extracts and other tars, and at least one antiallergic active, or b) at least c) at least one anti-inflammatory agent selected from the group consisting of sulfonated shale oils, bituminosulfonates, coal tar, coal tar extracts and other tars, at least one plant material with anti-inflammatory activity, and at least or (d) at least one anti-inflammatory agent comprising sulphonated shale oils, bituminous sulphonates, coal tar, coal tar extracts and other tars

Or at least one active substance selected from the group consisting of pantothenic acid and pantothenic acid derivatives, or e) at least one active substance having an antiinflammatory effect and at least one active substance selected from the group consisting of pantothenic acid and pantothenic acid derivatives, or f) at least one antiinflammatory substance, selected from the group consisting of sulphonated shale oils, bituminous sulphonates, coal tar, coal tar extracts and other tars, at least one antiallergic active, and at least one active substance selected from the pantothenic acid and pantothenic acid derivatives, or g) at least one herbal substance having an antiinflammatory effect, at least an anti-allergic active substance, and at least one active substance selected from the group comprising pantothenic acid and pantothenic acid derivatives, or h) at least one anti-inflammatory substance selected from the group consisting of sulphonated shale oils, bituminosulphonates, coal tar, coal tar extracts and other tars, at least one herbal substance having antiinflammatory activity, at least one antiallergic active, and at least one group comprising pantothenic acid and pantothenic acid derivatives Active ingredient includes.

A combination according to any one of the preceding claims, characterized in that said plant material is a single substance, a mixture of substances, a liquid or solid extract, a distillate or an oil obtainable from plants of any of the following genera or species include: borage, evening primrose, witch hazel, sunhat, chamomile, arnica, marigold, thyme, aloe vera, sage, mint, St. John's wort, rosemary, sea-buckthorn, cardiospermum halicacabum, myrrh, ratanhia, fennel, willow, yarrow, coltsfoot, comfrey, Devil's Claw, Bittersweet, Elderberry, Eucalyptus, Tea Tree, Tea Tree, Licorice, Melissa, Cilantro, Centaury, Nettle, Pineapple, Spruce, Pine, Oak.

A combination according to any one of the preceding claims, characterized in that the plant anti-inflammatory substance is selected from the group consisting of tannins, essential oils, azulene, proazulenes, bisabolols, bisabolites, flavonoids, flavones, anthocyanins, triterpenes, monoterpene alcohols, phenolic acids, Polyphenols, unsaturated fatty acids, hypericin, carotenoids, allantoin, bromelain, glycyrrhizin, glycyrrhizic acid and salts of glycyrrhizic acid.

7. Combination according to one of the preceding claims, characterized in that it contains at least one anti-inflammatory agent selected from the group consisting of vitamin A, carotenes, carotenoids, tretinoin, tocopherols (vitamin E) and biotin.

8. A combination according to any one of the preceding claims, characterized in that it contains a vegetable oil with anti-inflammatory effect, preferably selected from the evening primrose oil, borage oil and wheat germ oil group.

Combination according to any one of the preceding claims, characterized in that it contains at least one anti-inflammatory substance selected from the group comprising vegetable tanning agents and synthetic tanning agents.

10. A combination according to any one of the preceding claims, characterized in that the antiallergic drug (s) is / are selected from the group consisting of antihistamines, corticosteroids, synthetic mast cell degranulation inhibitors and leukotriene receptor antagonists.

1 1. A combination according to any one of the preceding claims, characterized in that it contains at least one active ingredient from the drug class of antihistamines and / or at least one active ingredient from the drug class of corticosteroids.

12. The combination according to claim 10 or 1 1, characterized in that the group of antihistamines ketotifen, thonzylamine, mepyramine, thenalidine, tripelennamine, chloropyramine, promethazine, tolpropamine, dimetinden, clemastine, bamipine, isothipendyl, diphenhydramine, Diphenhydrarninmethylbromid, chlorphenoxamine, pheniramine, Diphenylpyraline, dioxopromethazine, dimenhydrinate, thiethylperazine and meclozin, azelastine, levocabastine, astemizole, mebhydroline, terfenadine, mequitazine, cetirizine, emedastine, mizolastine, olopatadine, epinastine and antazoline.

13. A combination according to any one of claims 10 to 12, characterized in that the group of corticosteroids triamcinolone, dexamethasone, hydrocortisone, hydrocortisone acetate,

Hydrocortisone butyrate, Hydrocortisonbuteprat, prednisolone, betamethasone, methylprednisolone, clobetasone, Flumetason, Fluocortin, fluperolone, fluorometholone, fluprednidene, desonide, triamcinolone, alclometasone, dexamethasone, clocortolone, betamethasone, Fluclorolon, desoximetasone, fluocinolone, fluocortolone, diflucortolone, fludroxycortide, fluocinonide, budesonide, Diflorasone, amcinonide, halometasone, mometasone, methylprednisolone aceponate, beclomethasone, hydrocortisone aceponate, fluticasone, prednicarbate, difluprednate, ibetetasol, clobetasol, halcinonide, medrysone, desonide, formocortal, rimexolone, mazipredone, flunisolide and tixocortol.

14. Combination according to one of the preceding claims, characterized in that it contains at least one anti-allergic active substance which is selected from the group comprising cromoglycic acid, spaglumic acid, lodoxamide, nedocromil, montelukast and zafirlukast.

15. A combination according to any one of the preceding claims, characterized in that the group of pantothenic acid derivatives dexpanthenol, DL-panthenol, salts of pantothenic acid (eg Na-pantothenate, Ca-pantothenate), esters of pantothenic acid (eg. , Methyl ester), panthenol ethers (eg, ethyl or methyl ether), panthenol thioether, and pantylene triacetate, with dexpanthenol (= D - (+) - pantothenyl alcohol) being particularly preferred.

16. Combination according to one of the preceding claims, characterized in that it additionally contains one or more constituents which are selected from antibiotics, antiseptics,

,

Local anesthetics, Dekongestiva, skin care substances and sunscreen substances group is / are selected.

17. A combination according to any one of the preceding claims, characterized in that it additionally contains at least one component consisting of the urea, heparin, hyaluronic acid,

Glycine, lactic acid and its salts, pyroglutamic acid and salicylic acid group is selected.

18. Combination according to one of the preceding claims, characterized in that the combination is a fixed combination.

19. Medicaments containing a combination according to one of the preceding claims, characterized in that it is present as a solid, semi-solid, liquid or gaseous pharmaceutical form for topical application to the skin, mucosa or conjunctiva, preferably as a powder, powder, plaster, dust aerosol, granules, Lozenge, lozenge, chewing gum, gel, ointment, lotion, paste, shampoo, emulsion, suspension, solution, gargle, oil, spray, aerosol or inhalant.

20. Medicament according to one of the preceding claims, characterized in that it is a drug for intranasal, intraocular or dermal application.

21. Medicament according to one of claims 1 to 18, characterized in that it is a drug for topical application in the mouth and / or throat.

21. Medicament or combination according to one of the preceding claims for the treatment of diseases or disease symptoms of the skin, mucosa or conjunctiva, in particular for the treatment of symptoms that occur in any of the following allergic diseases: atopic eczema, psoriasis, contact dermatitis, skin allergies, contact dermatitis, photoallergic dermatitis, allergic urticaria, allergic rhinitis, allergic rhinoconjunctivitis, allergic conjunctivitis, allergic sinusitis, allergic laryngeal edema, allergic alveolitis, allergic bronchitis, allergic edema, allergic rosacea, insect bites, drug allergy, drug eruption, skin or subcutaneous infections, impetigo, abscesses, boils , Carbuncle; bullous dermatoses, in particular pemphigoid diseases; Lying, pruritus, decubitus, lupus, leg ulcers.

22. Use of a combination according to any one of claims 1 to 18 for the manufacture of a medicament for the treatment of diseases or disease symptoms of the skin, mucosa or conjunctiva, in particular for the treatment of symptoms that occur in any of the following diseases: atopic dermatitis, psoriasis, contact dermatitis, skin allergies, Contact dermatitis, photoallergic dermatitis, allergic urticaria, allergic rhinitis, allergic rhinoconjunctivitis, allergic conjunctivitis, allergic sinusitis, allergic laryngeal edema, allergic alveolitis, allergic bronchitis, allergic edema, allergic rosacea, insect bites, drug allergy, drug eruption, skin or subcutaneous infections, impetigo, abscesses , Boils, carbuncles; bullous dermatoses, in particular pemphigoid diseases; Lying, pruritus, decubitus, lupus, leg ulcers.

23. Use of a combination according to any one of claims 1 to 18 for the manufacture of a medicament for the treatment of allergic diseases or allergic symptoms of the nose.

24. Use of a combination according to any one of claims 1 to 18 for the manufacture of a medicament for the treatment of allergic diseases or allergic symptoms of the respiratory tract, in particular the throat, the trachea, the bronchi and bronchioles.

25. A method for the therapeutic treatment of a person who has one or more disease symptoms, in particular allergic symptoms, on the skin, mucosa or conjunctiva and requires therapeutic treatment, the method comprising administering a fixed active ingredient combination according to one of the preceding claims 1 to 18 in a therapeutically effective dose.