EP2164481A2

EP2164481A2 - Medicament comprising an active substance combination containing pantothenic acid or the derivatives thereof for the treatment of allergy symptoms

Info

Publication number: EP2164481A2
Application number: EP08773373A
Authority: EP
Inventors: Marianne Petersen-Braun; Sabine Rabini; Sabine GLÄSER; Marlene KLUTHE
Original assignee: Bayer Consumer Care AG
Current assignee: Bayer Consumer Care AG
Priority date: 2007-06-08
Filing date: 2008-06-07
Publication date: 2010-03-24
Also published as: WO2008148573A3; WO2008148573A2; RU2009148577A; BRPI0812750A2; RU2472499C2

Abstract

The invention relates to combinations comprising at least one active substance from the group encompassing pantothenic acid and pantothenic acid derivatives, particularly dexpanthenol, and at least one anti-allergic substance for the treatment of allergy symptoms of the skin or mucous membrane, medicaments containing said combinations, and the production thereof.

Description

Medicines containing a combination of active ingredients for the treatment of allergic symptoms

The invention relates to combinations comprising at least one active ingredient comprising pantothenic acid and pantothenic acid derivatives, in particular dexpanthenol, and at least one antiallergic active ingredient for the treatment of allergic symptoms of the skin or mucous membrane, medicaments containing them and their preparation.

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 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 of mucous membranes, allergic rhinitis, allergic bronchial asthma, allergic alveolitis, and allergic conjunctivitis.

Antihistamines and glucocorticoids are approved as both oral (ie systemic) and topical drugs for the treatment of allergic symptoms. Indeed the therapeutic efficacy of the known antihistamines and glucocorticoids is often inadequate, and an increase in the dose is not justifiable due to the associated risk of side effects. Frequently it comes in the symptomatic anti-allergic therapy using drugs from the classes of antimutamines and glucocorticoids to unwanted 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 pantothenic acid and its derivatives (eg dexpanthenol), but also by the amino acid glycine, cause an inhibition of the release of mediators from mast cells and thereby the allergic reaction can be alleviated.

Usually, dexpanthenol is used as a component in topical medicines. For example, EP 1159958 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 allergic symptoms of the skin or mucosa, 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 active ingredient from the pantothenic acid and pantothenic acid derivatives group, preferably dexpanthenol, and at least one anti-allergic active ingredient from the

Anti-inflammatory drugs, corticosteroids, synthetic mast cell degranulation inhibitors and leukotriene

Solved receptor antagonist comprehensive group. Surprisingly, it has been found that

Active ingredients from pantothenic acid and pantothenic acid derivatives comprising group, in particular dexpanthenol, the efficacy of the co-administered with the drug combination

Reinforcing antiallergic drugs in a synergistic way. This allows the dose of the

To reduce antiallergic drugs, compared to conventional medicines for symptomatic therapy of allergy, which does not contain dexpanthenol. Furthermore, surprisingly, a reduction of the side effects was found in comparison to the above-mentioned conventional medicaments. The combinations according to the invention are advantageously suitable for the treatment of allergic symptoms or diseases of the skin, the mucous membranes, especially the respiratory tract and in particular the nose, or even the conjunctiva. A combination of hydrocortisone with dexpanthenol is particularly advantageous for the treatment of allergic symptoms or diseases because of its anti-inflammatory properties.

The combinations according to the invention are furthermore advantageous, since they have a reduced side-effect potential. The occurrence of side effects such. B. Skin dryness can be significantly reduced due to the use of the drug combination according to the invention. This is particularly important because some anti-allergic drugs themselves can cause allergic reactions when applied topically, and a dose reduction is desirable for this reason. Additional advantages arise in the combinations according to the invention characterized in that dexpanthenol due to its anti-inflammatory properties inflammatory symptoms such. As redness, swelling and heat development and dry or burning mucous membranes, or crusting is able to reduce.

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 ranges, 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. The mentioned synergistic effect is observed in particular when the weight ratio of dexpanthenol (or pantothenic acid derivative) to said at least one anti-allergic active ingredient is in the range from 1: 100 to 100: 1, preferably in the range from 50: 1 to 1: 50, more preferably in the range of 1:10 to 10: 1.

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 in a proportion of 0.1 to 25 wt .-%, in particular 0.5 to 10 wt .-%, each based on the total active ingredient content, in the active ingredient combination.

Active hypoallergenic active substances which are used according to the invention in combination with dexpanthenol (or with pantothenic acid and / or pantothenic acid derivatives) are, in particular, active substances from the active substance class of the antihistamines and from the active substance class of the corticosteroids. The corticosteroids used according to the invention are generally glucocorticoids.

By the combined administration with dexpanthenol or with pantothenic acid and / or pantothenic acid derivatives, surprisingly, a synergistic increase in the therapeutic effect of the antihistamines as well as the glucocorticoid active ingredients can be achieved.

According to a further preferred embodiment, it is therefore provided that the combination according to the invention comprises at least one active ingredient from pantothenic acid and pantothenic acid derivatives group, preferably dexpanthenol, and at least one active ingredient from the drug class of antihistamines and / or at least one active ingredient from the class of corticosteroids.

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. Suitable antihistamines in connection with the present invention are, in particular, the following active substances: ketotifen, thonzylamine, mepyramine, thenalidine, tripelennamine, chlorpyramine, promethazine, tolpropamine, dimetindene, clemastine, bamipine, loratadine, isothipendyl, diphenhydramine, diphenhydramine methyl bromide, chlorphenoxamine, pheniramine, diphenylpyraline , Dioxopromethazine, dimenhydrinate, thiethylperazine and meclozin, 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 connection with the present invention, the following active substances 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, mazipredone, flunisolide and tixocortol. Particularly preferred corticosteroids are: hydrocortisone, beclomethasone dipropionate, dexamethasone.

The invention further includes embodiments which provide that the drug combination contains at least one synthetic antiallergic drug not selected from the group consisting of anti-viral and corticosteroids. In particular, active substances from the group comprising synthetic mast cell degranulation inhibitors and leukotriene receptor antagonists come 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 active substances exemplified in the preceding paragraphs do not provide a complete and exhaustive list of active substances from the classes of the antihistamines, glucocorticoids, synthetic mast cell degranulation inhibitors and leukotriene receptor Antagonists dar. The mention of these substances is only illustrative of these classes of drugs. 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. Particularly preferred are e.g. Salts with hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, propionic, lactic, tartaric, citric, fumaric, maleic, oxalic, succinic, butyric, decanoic, aspartic or benzoic acids.

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-ephenamine or methylpiperidine.

Preferably, the combination of active substances according to the invention comprises a) dexpanthenol and at least one antiWstaminic, or b) dexpanthenol, glycine and at least one antihistamine, or c) dexpanthenol and at least one corticosteroid, or d) dexpanthenol, glycine and at least one corticosteroid, or e) dexpanthenol, at least an antihistamine and at least one corticosteroid, or f) dexpanthenol, glycine, at least one antihistamine and at least one corticosteroid, or g) dexpanthenol and at least one group comprising the synthetic mast cell degranulation inhibitor and leukotriene receptor antagonists, or h) dexpanthenol, glycine and at least one drug selected from the group consisting of synthetic mast cell degranulation inhibitors and leukotriene receptor antagonists.

The active substance combinations described above may optionally additionally comprise at least one further active substance which is not selected from the abovementioned groups of the antiallergic active ingredients. The said further active ingredient may preferably consist of selected from the group consisting of herbal active substances, plant extracts (eg evening primrose oil, borage oil, St. John's wort extract, aloe vera extract, witch hazel extract, marigold extract, chamomile extract), herbal preparations, vitamins (eg vitamin E and its salts) , Tretinoin), dermatics (eg, urea, heparin, hyaluronic acid, allantoin, lactic acid and its salts, pyroglutamic acid, salicylic acid, tannins, coal tar solution, bisabolol, glycyrrhizic acid and its salts, bituminosulfonates such as ammonium bituminosulfonate or sodium bituminosulfonate) , Antibiotics (eg sulfonamides, erythromycin), antiseptics (eg chlorhexidine), local anesthetics (eg lidocaine, polidocanol), decongestants (eg sympathomimetics such as xylometazoline), as well as skin care substances (eg. Jojoba oil, aloe vera, lanolin, vegetable oils and fats) and sunscreen substances (UV-A filter, UV-B filter, broadband filter). Particularly advantageous is the addition of substances or mixtures of substances with anti-inflammatory effect, such as. Coal tar solution, sodium bituminosulfonate, ammonium bituminosulfonate, tretinoin, evening primrose oil, borage oil, St. John's wort extract, aloe vera extract, witch hazel extract, marigold extract, chamomile extract, vitamin E and its salts, bisabolol, allantoin, glycyrrhic acid and salts and polidocanol.

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.

"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 designed. 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 needed for the preparation of pharmaceutical formulations of the desired properties For example, viscosity increasing agents, pH adjuvants, 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. Dosage forms with controlled or protracted 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 modification of the

Composition of the drugs by known means, for example by means of

Envelopes, 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.

Preferably, the medicaments according to the invention are medicaments for intranasal, intraocular or dermal application, or medicaments for inhalation

Administration for the treatment of the respiratory tract (especially the bronchi) or for topical or oral use. As a result, the medicaments of the invention are particularly suitable for the treatment of allergic

Symptoms of the nasal mucosa, conjunctiva, skin, oral mucosa, mucous membrane of the pharynx, or lower respiratory tract (eg, trachea, bronchi,

Bronchioles).

According to a preferred embodiment, the present invention comprises dermal dosage forms containing dexpanthenol in combination with a Hl antihistamine. Preferred dosage forms are ointments, creams and gels. Preferred HIV antihistamines are bamipine, clemastine fumarate and chlorphenoxamine HCl. The dexpanthenol content is preferably in the range of 0.5 to 20 wt .-%, in particular from 5 to 15 wt .-%. The proportion of the antihistamine is preferably in the range of 0.01 to 10 wt .-%, in particular from 0.01 to 5 wt .-%. These dermal dosage forms can be used in particular for the treatment of allergic skin diseases or allergic symptoms of the skin. According to a further preferred embodiment, the invention comprises administration forms for intranasal or nasal administration which contain dexpanthenol in combination with a HI-antihistamine. Preferred administration forms are sprays, in particular dosing sprays, or solutions. Preferred Hl antihistamines are azelastine HCl and cromolyn sodium. The dexpanthenol content is preferably in the range from 0.5 to 20% by weight, in particular from 5 to 15% by weight. The proportion of the anti-micro-amine is preferably in the range from 0.01 to 10% by weight, in particular from 0.01 to 5% by weight. These dosage forms can be used in particular for the treatment of allergic diseases or allergic symptoms of the nose. Preferably, the administration is carried out by means of a dosing spray, wherein with each dosing a volume of 0.05 to 0.2 ml is administered.

According to another preferred embodiment, the invention includes dermal dosage forms containing dexpanthenol in combination with a corticosteroid. Preferred dosage forms are ointments, creams, gels, solutions and suspensions. Preferred corticosteroids are hydrocortisone, beclomethasone 17,21-dipropionate and dexamethasone. The dexpanthenol content is preferably in the range of 0.5 to 20 wt .-%, in particular from 5 to 15 wt .-%. The proportion of the corticosteroid is preferably in the range of 0.01 to 10 wt .-%, in particular from 0.01 to 5 wt .-%. These dermal dosage forms can be used in particular for the treatment of allergic skin diseases or allergic symptoms of the skin.

According to another preferred embodiment, the invention includes nasal administration dosage forms containing dexpanthenol in combination with a corticosteroid. Preferred dosage forms are ointments, sprays, aerosols, solutions and suspensions. Preferred corticosteroids are hydrocortisone, beclomethasone 17,21-dipropionate and dexamethasone. The dexpanthenol content is preferably in the range of 0.5 to 20 wt .-%, in particular from 5 to 15 wt .-%. The proportion of the corticosteroid is preferably in the range of 0.01 to 10 wt .-%, in particular from 0.01 to 5 wt .-%. These dosage forms can be used in particular for the treatment of allergic skin diseases or allergic symptoms of the nose.

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 make do with less than the abovementioned minimum quantity, 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 invention further extends to the use of a combination of active substances as defined above for the treatment of allergic symptoms of the skin, mucous membranes (in particular mucous membranes of the respiratory tract) or conjunctiva, and 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 allergic symptoms mentioned above are in particular those which occur in the following allergic diseases: atopic eczema, psoriasis, contact dermatitis, skin allergies, contact dermatitis, photoallergic dermatitis, allergic urticaria, allergic rhinitis (eg seasonal allergic rhinitis, perennial allergic Rhinitis), allergic rhinoconjunctivitis, allergic conjunctivitis, allergic sinusitis, allergic laryngeal edema, allergic alveolitis, allergic bronchitis, allergic edema, allergic rosacea, insect bites, drug allergy, drug rash.

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 mucosa; 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.

The invention further encompasses a method for the therapeutic treatment of a person having one or more allergic symptoms on the skin, mucous membranes (especially mucous membranes of the skin)

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.

Examples

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

A) Dermal administration forms containing dexpanthenol in combination with a Hl-antihistamine.

Example 1: Gel or Cream 2% by weight Bamipin

5% by weight of dexpanthenol

Excipients: purified water, macrogol (= polyethylene glycol), propylene glycol.

The gel or the cream is used for the treatment of allergic skin diseases, in particular of itchy skin diseases (eg urticaria). For application, the gel or cream is applied once or several times daily to the affected skin and massaged into the skin. Example 2: Gel or cream 0.04% by weight of clemastine fumarate 5% by weight of dexpanthenol Excipients: carbomer, propylene glycol, polyol fatty acid ester.

The gel or the cream is used for the treatment of allergic skin diseases, in particular of itchy skin diseases. The application is carried out as in Example 1.

Example 3: Cream 1.5% by weight chlorphenoxamine-HCl

5% by weight of dexpanthenol

Excipients: Purified Water, White Vaseline, Propylene Glycol, Medium Chain Triglycerides,

Macrogol fatty acid ester.

The cream is used for the treatment of allergic skin diseases, in particular itchy skin diseases. The application is carried out as in Example 1.

B) Dosage forms for intranasal or nasal administration containing dexpanthenol in combination with a Hl antihistamine.

Example 4: Nasal spray (dosing spray) or solution

0.1% by weight of azelastine HCl

5% 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. For application, one spray is injected into each nostril 1 to 3 times a day.

Example 5: Nasal spray (dosing spray) or solution 3.1% by weight of cromolyn sodium, 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 cromolyn sodium per spray. If the chosen spray volume is 0.14 ml (as in Example 4), the concentration of active compound is optionally adjusted accordingly (2 wt .-%) to obtain the specified single dose of 2.8 mg cromolyn sodium per spray.

The nasal spray is used to treat allergic rhinitis. For application, one spray is injected into each nostril 1 to 5 times a day.

C) Dosage forms containing dexpanthenol in combination with a corticosteroid.

Example 6: cream or ointment for dermal application 0.5% by weight hydrocortisone

5% by weight of dexpanthenol

additives:

Cream: white vaseline, isopropyl myristate, sorbitan monolaurate, propylene glycol, disodium

EDTA, purified water. Ointment: white vaseline, purified water, propylene glycol, liquid paraffin, wool wax.

The cream or ointment is used for the treatment of allergic skin diseases (eg eczema, in particular contact dermatitis, atopic dermatitis, dermatitis, urticaria, skin dermatoses). For application, the cream or ointment is applied once or several times daily to the affected areas of the skin and rubbed in lightly.

Example 7: Solution for dermal application 1% by weight of hydrocortisone 10% by weight of dexpanthenol Excipients: purified water, isopropyl alcohol, preservative (methyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate). Use and application: as in example 6.

Example 8: Suspension for dermal or nasal application 0.05% by weight of beclomethasone 17.21-dipropionate 5% by weight of dexpanthenol

Excipients: purified water, benzalkonium chloride, anhydrous glucose, phenylethyl alcohol, polysorbate 80.

The suspension described above can also be formulated as a pump spray, for example for use as a nasal spray. The suspension or spray is used for the prevention or treatment of allergic rhinitis. For application, one spray (0.09 ml) is sprayed into each nostril 2 to 5 times daily.

Example 9: Dosing aerosol for dermal or nasal application

0.1% by weight of beclomethasone 17,21-dipropionate

5% by weight of dexpanthenol

Excipients: ethanol, norflurane (1,1,1,2-tetrafluoroethane)

Spray volume: 0.05 ml.

Intranasal application: as in Example 8 (above).

Dermal use: The dosing aerosol is used to treat allergic dermatitis or allergic dermatitis. For application, the aerosol is sprayed 2 to more times daily on the affected skin.

Example 10: Nose Ointment

0.2% by weight of dexamethasone

3 to 5% by weight of dexpanthenol

Excipients: white Vaseline, paraffin, wool wax, purified water.

The nose ointment is used to treat allergic rhinitis. For use, an approximately pea-sized amount is introduced into each nostril and distributed by massaging from the outside.

Example 11: Nasal spray (dosing spray) or solution 3.5% by weight of dexpanthenol

Excipients: sterile isotonic seawater, potassium dihydrogen phosphate,

Potassium monohydrogen phosphate

The nasal spray is used for the treatment of allergic rhinitis and / or allergic rhinitis and is contemporaneous or delayed with other preparations containing at least one anti-allergic drug from the group of antihistamines, corticosteroids, synthetic mast cell degranulation inhibitors and / or leukotriene receptor anatagonists to apply. For application, one spray is sprayed into each nostril 1 to 5 times a day. First clinical findings - open observation:

The effect of a dexpanthenol nasal spray from Example 11 containing 3.5% dexpanthenol was tested on five patients suffering from diagnosed hay fever (grass pollinosis).

All patients were premedicated with either a topical antiallergic spray (azelastine) or an oral antiallergic drug (cetirizine) at the recommended doses (azelastine: up to 2 nasal applications per day, cetirizine 10 mg once daily). In a severe case, both antiallergic agents were used.

The observed symptoms, such as runny or stuffy nose, sneezing, watery eyes, red and inflamed skin in and around the nose were classified as moderate to severe (depending on the time interval to taking the medication).

The patients also complained of nose dryness and nosebleeds. These symptoms have been attributed to the use of the antiallergic drugs whose side effects are well known.

Patients were encouraged to use the dexpanthenol nasal spray of Example 11 in situations in which they were exposed to high doses of an allergen (e.g., when crossing a field of flowering grasses) in addition to their ingested antiallergic medication. About two to three applications were reported.

findings:

Two patients using azelastine alone to treat their symptoms reported that the use of the dexpanthenol-containing nasal spray of Example 11 improved symptoms of nasal dryness and inflammation of the skin in and around the nose and a reduction in the symptoms of on-going and stuffy nose led. They were able to reduce the application of azelastine from two applications daily to one application. Three patients taking cetirizine reported an improvement in the symptoms of dryness or chapped skin, less inflammatory response of the skin in and around the nose, and reduced allergic rhinitis. An extension of the time interval between tablet intake of cetirizine became possible.

Conclusion:

These initial findings confirm the synergistic effect of dexpanthenol with antiallergic agents when used in combination.

In addition, dexpanthenol moisturizes the epidermis and mucosa, reducing side effects such as dryness of the nose or nosebleeds, which often occur during the application of antiallergic drugs or antihistamines, and thus improves it

Side effect profile of the corresponding active ingredients.

Claims

claims:

A combination comprising at least one active substance comprising pantothenic acid and pantothenic acid derivatives and at least one anti-allergic active ingredient from the antihistamines, corticosteroids, synthetic mast cell degranulation inhibitors and leukotriene receptor antagonists.

2. Combination according to claim 1, characterized in that the active substance from pantothenic acid and pantothenic acid derivatives comprising dexpanthenol group.

3. Combination according to claim 1 or 2, characterized in that the combination additionally contains glycine.

4. Combination according to one of claims 1 to 3, characterized in that it comprises at least one active ingredient from pantothenic acid and pantothenic acid derivatives

Group, and at least one drug from the drug class of antihistamines or / and at least one drug from the drug class of corticosteroids.

5. Combination according to one of the preceding claims, characterized in that it additionally comprises one or more constituents selected from the herbal active substances,

Plant extracts, herbal preparations, vitamins, dermatics, antibiotics, antiseptics, local anesthetics, Dekongestiva, skin care substances and sunscreen substances are selected.

6. Combination according to one of the preceding claims, characterized in that the combination contains at least one active substance from the drug class of antihistamines, preferably selected from the ketotifen, thonzylamine, mepyramine, thenalidine, tripelennamine, chloropyramine, promethazine, tolpropamine, dimetinden, clemastine, bamipin , Isothipendyl, Diphenhydramine, Diphenhydraminemethylbromide, Chloφhenoxamine, Pheniramine, Diphenylpyralin, Dioxopromethazine, Dimenhydrinat, Thiethylperazine and Meclozin, Azelastine, Levocabastine, Astemizole, Mebhydroline, Terfenadine, Mequitazine, Cetirizine, Emedastine, Mizolastine, Olopatadine, Epinastine and Antazoline group of antihistamines.

7. A combination according to any one of the preceding claims, characterized in that the combination contains at least one active substance from the drug class of corticosteroids, preferably selected from the triamcinolone, dexamethasone, hydrocortisone,

Hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone buteprate, 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-containing group of corticosteroids.

8. A combination according to any one of the preceding claims, characterized in that the combination contains at least one synthetic anti-allergic active substance, not from the

Antihistamines and corticosteroids comprehensive group is selected.

9. A combination according to claim 8, characterized in that said antiallergic agent is selected from the group comprising synthetic mast cell degranulation inhibitors and leukotriene receptor antagonists, preferably from the group comprising cromoglycic acid, spaglumic acid, lodoxamide and nedocromil.

10. A combination according to any one of the preceding claims, characterized in that the combination a) dexpanthenol and at least one antihistamine, or b) dexpanthenol, glycine and at least one antihistamine, or c) dexpanthenol and at least one corticosteroid, or d) dexpanthenol, Or dexpanthenol, at least one antihistamine and at least one corticosteroid, or f) dexpanthenol, glycine, at least one antihistamine and at least one corticosteroid, or g) dexpanthenol and at least one of the synthetic mast cell degranulation inhibitors and leukotriene Receptor antagonists comprising a group selected drug, or h) dexpanthenol, glycine and at least one drug selected from the group comprising synthetic mast cell degranulation inhibitors and leukotriene receptor antagonists.

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

12. 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 dosage 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.

13. Medicament according to claim 12, characterized in that it is a drug for intranasal, intraocular or dermal application.

14. Medicament according to one of claims 12 to 13, characterized in that it is a drug for topical application in the mouth and / or throat.

15. A pharmaceutical or combination according to any one of claims 1 to 14 for the treatment of allergic 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 rash.

16. Use of a combination according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of allergic symptoms of the skin, mucosa or conjunctiva, in particular for the treatment of symptoms that occur in any of the following 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.

17. Use of a combination according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of allergic diseases or allergic symptoms of the nose.

18. Use of a combination according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of allergic diseases or allergic symptoms of the respiratory tract, in particular of the throat, the trachea, the bronchi and bronchioles.

19. A method for the therapeutic treatment of a person who has one or more allergic symptoms on the skin, mucosa or conjunctiva and requires therapeutic treatment, said method comprising administering a combination of active agents according to any one of the preceding claims 1 to 11 in a therapeutically effective dose ,