MX2008007568A - Use of tiotropium salts in the treatment of moderate persistent asthma - Google Patents

Abstract

The instant invention relates to the use of tiotropium salts for the manufacture of a medicament for the treatment of patients suffering from moderate persistent asthma.

Description

USE OF TIOTROPY SALTS IN THE TREATMENT OF MODERATE PERSISTENT ASTHMA The present invention relates to the use of tiotropium salts for the preparation of a medicament for the treatment of patients suffering from moderate persistent asthma. BACKGROUND OF THE INVENTION Asthma is one of the most common chronic diseases in the world. It is a chronic inflammatory disorder of the respiratory tract. Asthma produces recurrent episodes of syphilinity, tightness in the chest, shortness of breath and cough. Asthma attacks (or exacerbations) are episodic, but inflammation of the airways is present chronically. It is known that asthma can appear at different levels of severity. The severity of asthma may be intermittent, or asthma may be persistently mild, moderate or severe. The severity varies among individuals, not necessarily related to the frequency or persistence of symptoms and may change in an individual over time. Decisions about treatment are made based on severity and vice versa, the severity classification level is based on medication therapy. In accordance with the globally accepted guidelines of the GINA (Global Initiative for Asthma), the severity of asthma can be classified in the so-called stages 1 to 4 of the GINA. The severity of asthma determines the necessary treatment (see: GINA - Pocket guide for asthma management and prevention as updated 2005). In many patients, medication must be taken every day to control symptoms, to improve lung function and to prevent attacks. Optionally, medications are also required to alleviate acute symptoms such as wheezing, tightness in the chest and coughing. Stage 1 asthma of GINA is also called intermittent asthma. Symptoms usually appear less than once a week. Stage 1 asthma from GINA usually does not require daily medication. In mild persistent asthma (stage 2 of the GINA), the recommended medication is the treatment with inhaled corticosteroids in low doses.

For moderate persistent asthma (stage 3 of the GINA), the administration of corticosteroids in low to medium doses in combination with long-acting inhaled beta-2-agonists is recommended. Finally, severe persistent asthma (stage 4 of GINA) is usually treated with inhaled corticosteroids in high doses in combination with long-acting inhaled beta-2-agonists plus one or more of the following substances, if necessary: theophylline slow release, leukotriene modifier, long-acting oral beta-2-agonist and oral corticosteroids. The object of the present invention is to provide an alternative treatment for patients suffering from moderate persistent asthma (stage 3 of GINA). Another object of the invention is to provide pharmaceutical compositions suitable for the treatment of these patients. Description of the invention The present invention relates to the use of tiotropium 1 salts for the preparation of a medicament for the treatment of patients suffering from moderate persistent asthma. The compound tiotropium bromide is known from the European patent application EP 418716 A1 and has the chemical structure: wherein X "denotes bromide Within the scope of the present invention, the term tiotropium should be considered as a reference to free cation V. By tiotropium salts which can be used within the scope of the present invention, compounds which contain, in addition to tiotropium V as a counterion, are understood to be an anion X "with a single negative charge, preferably an anion selected from chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluene sulfonate, although chloride, bromide, iodide, sulfate, are preferred as counterions, methanesulfonate or p-toluenesulfonate. Of all the salts, chloride, bromide, iodide and methanesulfonate are particularly preferred. The tiotropium bromide has an extraordinary importance according to the invention, preferably in the form of the crystalline tiotropium bromide monohydrate which is described in WO 02/30928. In another preferred embodiment, anhydrous tiotropium bromide is used within the scope of the invention as described in WO 03/000265 or WO 05/042527. Of these two anhydrous forms, the one described in WO 05/042527 is of special interest. Within the scope of the invention, the expression "moderate persistent asthma" should be understood as "asthma" as the severity of stage 3 of GINA. Asthma in stage 3 of GINA severity is characterized by daily symptoms for a long time or nocturnal asthma more than once a week. A patient with a reference PEF in the pretreatment of more than 60 percent, but less than 80 percent of the best expected or best staff and a PEF variability of 20 to 30 percent. If the patient's asthma is not controlled at a low dose of inhaled glucocorticosteroids (Stage 2), then asthma should also be considered moderate persistent. The PEF (maximum expiratory flow) values can be measured with maximum flow meters known in the art. To measure the so-called forced expiratory volume in 1 second (FEV-i), spirometers known in the art are used. The methods for the determination of PEF and FEVi are well proven in the art. The invention also relates to the use of tiotropium salts for the preparation of a medicament for the treatment of patients suffering from asthma with a stage 3 severity of GINA. The invention also relates to the use of tiotropium salts for the preparation of a medicament for the treatment of asthma in patients suffering from daily symptoms. The invention also relates to the use of tiotropium salts? for the preparation of a medication for the treatment of asthma in patients suffering from exacerbations. The invention also relates to the use of tiotropium 1 salts for the preparation of a medicament for the treatment of asthma in patients suffering from nocturnal asthma symptoms. The invention also relates to the use of tiotropium 1 salts for the preparation of a medicament for the treatment of asthma in patients with limited physical activity. The invention also relates to the use of tiotropium 1 salts for the preparation of a medicament for the treatment of asthma in patients with PEF values of 60 to 80%. The invention also relates to the use of tiotropium 1 salts for the preparation of a medicament for the treatment of asthma in patients with FEVi values <; 80% The invention also relates to the use of tiotropium 1 salts for the preparation of a medicament for the treatment of asthma in patients with a PEF variability of 20 to 30%. Furthermore, the present invention relates to a method for the treatment of patients suffering from moderate persistent asthma, comprising the administration of a therapeutically effective amount of a tiotropium salt. The invention also relates to a method for the treatment of patients suffering from asthma with a severity of stage 3 of GINA, comprising the administration of a therapeutically effective amount of a salt of tiotropium γ. The invention also relates to a method for the treatment of patients suffering from asthma with daily symptoms, comprising administering a therapeutically effective amount of a tiotropium salt 1_. The invention also relates to a method for the treatment of patients suffering from asthma with frequent exacerbations, comprising the administration of a therapeutically effective amount of a tiotropium salt 1. The invention also relates to a method for the treatment of patients who they suffer from asthma with nocturnal symptoms, which comprises the administration of a therapeutically effective amount of a tiotropium salt 1_. The invention also relates to a method for the treatment of patients suffering from asthma with limited physical activity, comprising the administration of a therapeutically effective amount of a tiotropium salt 1_. The invention also relates to a method for the treatment of patients suffering from asthma with PEF values < 80%, which comprises the administration of a therapeutically effective amount of a tiotropium salt? . The invention also relates to a method for the treatment of patients suffering from asthma with FEV-i < 80%, which comprises the administration of a therapeutically effective amount of a tiotropium salt 1. The invention also relates to a method for the treatment of asthma in patients with a PEF variability of 20 to 30%, comprising the administration of a therapeutically effective amount of a tiotropium salt? . Asthmatics with homozygotes for the Arg / Arg genotype at codon 16 of the beta2-adrenoreceptor gene (ADRB2) on chromosome 5 are particularly useful in treatment with tiotropium because betamimetic is not as effective as in patients with a "natural" genotype (p. eg Gly / Gly). Accordingly, the invention also relates to a method for the treatment of moderate persistent asthma (GINA stage 3) in patients with homozygosity for the Arg / Arg genotype at codon 16 of the beta2-adrenoceptor gene (ADRB2) on chromosome 5 In another preferred embodiment the invention relates to a method for the treatment of moderate persistent asthma (stage 3 of GINA) in patients carrying the SNP Arg / Arg (Single Nucleotide Polymorphism). In another preferred embodiment the invention relates to a method for the treatment of moderate persistent asthma (GINA stage 3) in patients carrying the Arg / Arg SNP (Single Nucleotide Polymorphism) as a second reference therapy . In another preferred embodiment the invention relates to a method for the treatment of moderate persistent asthma in patients of stage 3 of GINA with the genotype Arg / Arg.

The expression "homozygosis for the Arg / Arg genotype at codon 16 of the beta2-adrenoreceptor gene (ADRB2) on chromosome 5" should be understood as describing a population of patients, which is affected by a single-nucleotide mutation in a proportion from approximately 15 to 20% of the general population. Numerous studies have described associations of ADRB2 polymorphisms with asthma. Recent studies revealed in patients who were homozygous (ie, the alleles in a genetic locus are identical) for arginine at the 16th amino acid position a detrimental response to the regular use of β2-agonist. Patients in stage 3 of GINA with the Arg / Arg genotype are patients who are still instructed to use inhaled glucocorticosteroids of short to medium action plus a long-acting inhaled beta-2-agonist, according to the existing indications. Patients who carry the Arg / Arg SNP (single nucleotide polymorphism) are patients who are presumed to have an inadequate treatment response to a second controller therapy such as long-acting beta-2-agonists. There is evidence that tiotropium bromide as a long-acting anticholinergic may be a treatment option in patients with moderate persistent asthma and is administered as an alternative control medication without presenting unfavorable side effects. The term "therapeutically effective amount" will mean the amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human being, which is sought by the researcher or physician.

For moderate and persistent asthma, medical treatment with corticosteroids is recommended. However, patients with moderate persistent asthma often show symptoms daily for a prolonged period despite treatment with inhaled corticosteroids. Therefore, in another embodiment, the invention relates to the use of tiotropium salts? for the preparation of a drug for the treatment of moderate persistent asthma in patients who show persistent symptoms despite treatment with inhaled beta-agonist. For moderate and persistent asthma, medical treatment with beta-2-agonists is also recommended, particularly with long-acting inhaled beta-2-agonists. However, patients suffering from moderate persistent asthma often have symptoms daily for a prolonged period despite treatment with inhaled beta-2-agonists. Therefore, in another embodiment, the invention relates to the use of tiotropium salts for the preparation of a medicament for the treatment of moderate persistent asthma in patients with persistent symptoms despite treatment with inhaled beta-2-agonists. For the medical treatment of moderate and persistent asthma, medical treatment with corticosteroids in combination with long-acting beta-2-agonists is recommended as primary control therapy. However, patients with moderate persistent asthma often have asthma symptoms on a daily basis despite treatment with inhaled corticosteroids in combination with long-acting beta-2-agonists. Therefore, in another embodiment, the invention relates to the use of tiotropium salts for the preparation of a medicament for the treatment of moderate persistent asthma in patients who present symptoms daily despite treatment with corticosteroids and beta-2. - Long-acting inhaled agonists. In still another preferred embodiment, the invention relates to the use of tiotropium salts for the preparation of a medicament for the maintenance treatment of moderate persistent asthma and the prevention of broncho-obstructive symptoms in patients who are not adequately controlled by a patient. maintenance control treatment with inhaled corticosteroids and long-acting beta-2-agonists. In another preferred embodiment still, the invention relates to the use of tiotropium salts for the preparation of a medicament for the maintenance treatment of asthma with a severity of stage 3 of the GINA and the prevention of broncho-obstructive symptoms in patients who are not adequately controlled for a maintenance control treatment with inhaled corticosteroids and long-acting beta-2-agonists. In still another preferred embodiment, the invention relates to the use of tiotropium salts for the preparation of a medicament intended for second line maintenance control therapy for the treatment of moderate persistent asthma. In still another preferred embodiment, the invention relates to the use of tiotropium salts for the preparation of a medicament for the maintenance treatment of moderate persistent asthma and the prevention of broncho-obstructive symptoms in patients who already receive a maintenance control treatment. with inhaled corticosteroids. In still another preferred embodiment, the invention relates to the use of tiotropium 1 salts for the preparation of a medicament for the maintenance treatment of asthma in stage 3 of GINA and the prevention of broncho-obstructive symptoms in patients who already receive a maintenance control treatment with inhaled corticosteroids. In still another preferred embodiment, the invention relates to the use of tiotropium salts for the preparation of a medicament for the maintenance treatment of moderate persistent asthma and the prevention of broncho-obstructive symptoms in patients who already receive a maintenance control treatment. with inhaled corticosteroids, in which the inhaled corticosteroid is selected from prednisolone, prednisone, butixocortpropionate, RPR-106541, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, 6a, 9a-difluoro -17β - [(2-furanylcarbonyl) oxy] -11β-hydroxy-16a-methyl-3-oxo-androsta-1,4-diene-17β-carbonate (S) -fluoromethyl, 6a, 9a-difluoro- 11β-hydroxy-16α-methyl-3-oxo-17a-propionyloxy-androsta-1,4-diene-17β-carbothionate (S) - (2-oxo-tetrahydro-furan-3S-yl) and ethylamine dichloroacetate ( BNP-166), optionally in the form of racemates, enantiomers or diastereomers of the and, optionally in the form of the salts and derivatives thereof, solvates and / or hydrates thereof. In still another preferred embodiment, the invention relates to the use of tiotropium salts for the preparation of a medicament for the maintenance treatment of severe persistent asthma and the prevention of broncho-obstructive symptoms in patients who already receive a maintenance control treatment. with inhaled corticosteroids, wherein the inhaled corticosteroid is selected from flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, 6a, 9a-difluoro-17a - [(2-furanylcarbonyl) -oxi] -11-β-hydroxy-16a-methyl-3-oxo-androsta-1,4-diene-17β-carbonate (S) -fluoromethyl, 6a, 9a-difluoro-11β-hydroxy-16a-methyl- 3-Oxo-17a-propionyloxy-androsta-1,4-diene-17β-carotationate (S) - (2-oxo-tetrahydro-furan-3S-yl) and ethy-phenol dichloroacetate, optionally in the form of the racemates, enantiomers or diastereomers thereof and, optionally, in the form of the salts and derivatives of the same, the solvates and / or hydrates thereof. In still another preferred embodiment, the invention relates to the use of tiotropium 1 salts for the preparation of a medicament for the maintenance treatment of moderate persistent asthma and the prevention of broncho-obstructive symptoms in patients who already receive a control treatment of maintenance with inhaled corticosteroids, in which the inhaled corticosteroid is selected from budesonide, fluticasone, mometasone, ciclesonide, 6a, 9a-difluoro-17a - [(2-furanylcarbonyl) oxy] -11β-hydroxy-16a-methyl-3- oxo-androsta-1, (S) -fluoromethyl 4-diene-17β-carbothionate and ethy-phenol dichloroacetate, optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and derivatives thereof, to the solvates and / or hydrates thereof. Any reference to the spheroids includes a reference to any of the salts or derivatives, hydrates or solvates thereof that may exist. Examples of possible salts and derivatives of steroids may be: alkali metal salts, such as sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dibasic phosphates, palmitates, pivalates or furoates. In another still preferred embodiment, the invention relates to the use of tiotropium 1 salts for the preparation of a medicament intended for the maintenance treatment of moderate persistent asthma and the prevention of broncho-obstructive symptoms in patients carrying the Arg / Arg genotype. codon 16 (chromosome 5) already receiving a maintenance control treatment with inhaled corticosteroids and long-acting beta-2-agonists, in which the long-acting beta-2-agonist is selected from albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetarine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, TD 3327, ritodrine, salmeterol, salmefamol, soterenot, sulfonterol, thiaramide, terbutaline , tolubuterol, CHF-4226 (= TA 2005 or carmoterol; ), HOKU-81, KUL-1248, 3- (4-. {6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -hexyloxy] -butyl) - benzenesulfonamide, 5- [2- (5,6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl] -8-hydroxy-1 / - / - quinolin-2-one, 4-hydroxy-7 -[2-. { [2-. { [3- (2-phenylethoxy) propyl] sulfonyl} ethyl] -amino} ethyl] -2 (3H) -benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1 - [3- (4 -methoxy-benzylamino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H -1, 4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propyl-amino] ethanol, 1 - [2H-5-hydroxy-3- oxo-4H-1, 4-benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1 - [2H-5-hydroxy-3-oxo-4H -1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol, 1 - [2H-5-hydroxy-3-oxo-4H- 1,4-benzoxazin-8-yl] -2-. { 4- [3- (4-methoxyphenyl) -1,2,4-triazol-3-yl] -2-methyl-2-butylamino} ethanol, 5-hydroxy-8- (1-hydroxy-2-isopropyl-aminobutyl) -2H-1,4-benzoxazin-3- (4H) -one, 1- (4-amino-3-chloro-5-trifluoromethylphenyl) ) -2-tert-butylamino) ethanol, 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol and N- [2-hydroxy-5- (1-hydroxy-2) - { 2- [4- (2-Hydroxy-2-phenyl-ethylamino) -phenyl] -ethylamino] -ethyl) -phenyl] -formamide, optionally in the form of racemates, enantiomers, diastereomers and optionally salts of addition of pharmacologically acceptable acids and hydrates thereof. In another preferred embodiment, the invention relates to the use of tiotropium 1 salts for the preparation of a medicament for the maintenance treatment of severe persistent asthma and the prevention of broncho-obstructive symptoms in patients carrying the Arg / Arg genotype in the codon 16 (chromosome 5) that already receive a maintenance control treatment with inhaled corticosteroids and long-acting beta-2-agonists, in which the long-acting beta-2-agonist is selected from bambuterol, bitolterol, carbuterol, clenbuterol , fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, TD 3327, salmeterol, sulfonterol, terbutaline, tolubuterol, CHF-4226 (= TA 2005 or carmoterol;), 3- (4- { 6- [2 -hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -hexyloxy.] - butyl) -benzenesulfonamide, 5- [2- (5,6-diethyl-indan-2-ylamino) -1 -hydroxy-ethyl] -8-hydroxy-1 / - / - quinolin-2-one, 4-hydroxy-7- [2-. { [2-. { [3- (2-phenyl-ethoxy) propyl] sulfonyl} ethyl] -amino} ethyl] -2 (3H) -benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [3- (4 -methoxy-benzyl-amino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino-ethanol, 1 - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin -8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol, 1 - [2 H -5-hydroxy-3-oxo-4H-1, 4- benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8] -yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] -ethanol, 1 - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8] -il] -2-. { 4- [3- (4-methoxyphenyl) -1,2,4-triazol-3-yl] -2-methyl-2-butylamino} ethanol, 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazin-3- (4H) -one, 1- (4-amino-3-chloro-5-trifluoromethylphenyl) - 2-tert-butylamino) ethanol, 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol and N- [2-Hydroxy-5- (1-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl-ethylamino) -phenyl] -ethylamino} -ethyl) -phenyl] -formamide, optionally in the form of the racemates, the enantiomers, the diastereomers and optionally the pharmacologically acceptable acid addition salts and the hydrates thereof. In still another preferred embodiment, the invention relates to the use of tiotropium 1 salts for the preparation of a medicament for the maintenance treatment of moderate persistent asthma and the prevention of broncho-obstructive symptoms in patients bearing the Arg / Arg genotype. codon 16 (chromosome 5) already receiving a maintenance control treatment with inhaled corticosteroids and long-acting beta-2-agonists, in which the long-acting beta-2-agonist is selected from fenoterol, formoterol, salmeterol, CHF-4226 (= TA 2005 or carmoterol; ), 3- (4-. {6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -hexyloxy}. Butyl) -benzenesulfonamide, 5- [2- ( 5,6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl] -8-hydroxy-1 H -quinolin-2-one, 1- [3- (4-methoxybenzyl-amino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butyl-amino] ethanol, 1 - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] - 2- [3- (4-N, N-dimethylamino-phenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8- il] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1 - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] - 2- [3- (4-n-Butyloxyphenyl) -2-methyl-2-propylamino-ethanol, 1 - [2 H -5-hydroxy-3-oxo-4 H-1,4-benzoxazin-8-yl] -2-. { 4- [3- (4-methoxyphenyl) -1,2,4-triazol-3-yl] -2-methyl-2-butylamino} ethanol and N- [2-Hydroxy-5- (1-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl-ethylamino) -phenyl] -ethylamino} -ethyl) -phenyl ] -formamide, optionally in the form of racemates, enantiomers, diastereomers and optionally the pharmacologically acceptable acid addition salts and the hydrates thereof. Of the betamimetics mentioned above, the compounds formoterol, salmeterol, CHF-4226 (= TA 2005 or carmoterol;), 3- (4-. {6- [2-hydroxy-2- (4-hydroxy-3-) are preferred. hydroxymethyl-phenyl) -ethylamino] -hexyloxy.] - butyl) -benzenesulfonamide, 5- [2- (5,6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl] -8-hydroxy-1H -quinolin-2-one and N- [2-Hydroxy-5- (1-hydroxy-2- { 2- [4- (2-hydroxy-2-phenyl-ethylamino) -phenyl] - is particularly preferred. ethylamino.} - ethyl) -phenyl] -formamide, optionally in the form of racemates, enantiomers, diastereomers and optionally pharmacologically acceptable acid addition salts thereof, and hydrates thereof. Examples of pharmacologically acceptable acid addition salts of the beta-2-agonists according to the invention are the pharmaceutically acceptable salts selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid. , fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1-hydroxy-2-naphthalenecarboxylic acid, 4-phenycinnamic acid, 5- (2,4-difluorophenyl) salicylic acid or maleic acid. If desired, mixtures of the acids mentioned above can also be used to prepare the salts. According to the invention, the salts of the beta-2-agonists selected from the hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate, 4-phenylcinnamate, 5- (2,4-difluorophenyl) salicylate, maleate and xinafoate are preferred. . In the case of salmeterol, the salts selected from hydrochloride, sulfate, 4-phenylcinnamate, 5- (2,4-difluorophenyl) salicylate and xinafoate, of which 4-phenylcinnamate, 5- (2) are especially important, are especially preferred. , 4-difluorophenyl) salicylate and especially the xinafoate. In the case of formoterol, the salts selected from hydrochloride, sulfate, hemifumarate and fumarate are especially preferred, of which hydrochloride, hemifumarate and fumarate are particularly preferred. According to the invention, formoterol fumarate dihydrate or formoterol hemifumarate hydrate are of exceptional importance. Any reference to the term beta-2-agonists also includes a reference to the enantiomers and relevant mixtures thereof. In another embodiment still the invention, relates to the use of tiotropium salts 1 for the preparation of a medicament for the treatment of moderate persistent asthma in which the patients are children, preferably children under 14, more preferably less than 10, even more preferably under 8, preferably under 6 years. In a particular preferred embodiment, children are less than 5 years old. In another aspect, the present invention relates to the aforementioned use of tiotropium salts in which for each individual dose preferably preferably 1-20 pg, more preferably 2 -15 pg tiotropium Y is preferably administered. In another aspect, the present invention refers to the aforementioned use of tiotropium 1 salts in which for each individual dose, 5-10 μg of tiotropium are administered. In another aspect, the present invention relates to the aforementioned use wherein the salts of tiotropium 1 are administered once or twice, preferably once a day. In another aspect, the present invention relates to the aforementioned use, wherein the salts of tiotropium? they are administered in the morning or in the afternoon. The use of tiotropium salts 1 according to the invention includes the use of the solvates and hydrates formed in this way, preferably the hydrates, and more preferably the monohydrates. Based on the amounts of the active substance tiotropium administered per unit dose as specified hereinbefore, one skilled in the art can easily calculate the corresponding amount of, for example, tiotropium bromide and / or tiotropium bromide monohydrate. The tiotropium salts 1 are preferably administered according to the invention by inhalation. For this purpose, the tiotropium 1 salts have to be prepared in inhalable forms. Inhalable preparations include inhalable powders, metering aerosols containing propellants or inhalable solutions without propellants. The inhalable powders according to the invention containing the tiotropium salts? optionally they are mixed with physiologically acceptable excipients. Within the scope of the present invention, the term inhalable non-propellant solutions also includes ready-to-use sterile inhalable concentrates or solutions. Formulations that can be used within the scope of the present invention are described in more detail in the following part of the specification. In accordance with the invention, inhalable powders containing 0.01 to 2% tiotropium are preferred. Particularly preferred inhalable powders for use within the invention contain tiotropium in an amount of about 0.03 to 1%, preferably 0.05 to 0.6%, particularly preferably 0.06 to 0.3%. Finally, inhalable powders containing approximately 0.08 to 0.22% tiotropium are of particular importance according to the invention. The amounts of tiotropium already specified are based on the amount of tiotropium cation contained. The excipients that are used for the purposes of the present invention are prepared by grinding or sieving, using current methods known in the art. The excipients used according to the invention can also be mixtures of excipients which are obtained by mixing fractions of excipients of different average particle sizes. Examples of physiologically acceptable excipients that can be used to prepare the inhalable powders for use in capsules for inhalation according to the invention include monosaccharides (eg, glucose, fructose or arabinose), disaccharides (eg, lactose, sucrose, maltose, trehalose), oligo- and polysaccharides (eg, dextrans, dextrins, maltodextrin, starch, cellulose), polyalcohols (eg, sorbitol, mannitol, xylitol), cyclodextrins (eg, -cyclodextrin, β-cyclodextrin, β-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin), amino acids (eg, arginine hydrochloride) or salts (eg, sodium chloride, calcium carbonate) ), or their mixtures. Preferably, mono or disaccharides are used, although the use of lactose or glucose, in particular, but not exclusively, in the form of their hydrates is preferred. For the purposes of the invention, lactose is the excipient especially preferred. Within the scope of the inhalable powders according to the invention the excipients have a maximum average particle size of up to 250 μm, preferably between 10 and 150 μm, most preferably between 15 and 80 μm. Sometimes it may be appropriate to add to the excipient mentioned above finer fractions of excipient with an average particle size of 1 to 9 μm. These finer excipients are also selected from the group of possible excipients listed hereinabove. The average particle size can be determined using methods known in the art (as for example in WO 02/30389, paragraphs A and C). Finally, in order to prepare the inhalable powders according to the invention, the micronized crystalline non-hydrated tiotropium bromide, preferably characterized by an average particle size of 0.5 to 10 μm, particularly preferably between 1 and 5 μm, is added to the mixture of excipients (as for example in WO 02/30389, paragraph B). The processes for grinding and micronizing active substances are known from the prior art. If a specifically prepared excipient mixture is used as an excipient, it is particularly preferred to use excipients having an average particle size of 10-50 μm and 10% fine content of 0.5 to 6 μm. By average particle size is meant here the value of 50% of the volume distribution measured with a laser diffractometer using the dry dispersion method. The average particle size can be determined using methods known in the art (as for example in WO 02/30389, paragraphs A and C). Similarly, the 10% fine content in this case refers to the value of 10% of the volume distribution measured using a laser diffractometer. In other words, for the purposes of the present invention, the 10% fine content indicates the particle size below which 10% of the amount of particles is located (based on the volume distribution). The percentages expressed within the scope of the present invention are always percentages by weight, unless otherwise specified. In particularly preferred inhalable powders, the excipient is characterized by an average particle size of 12 to 35 μm, particularly preferably 13 to 30 μm. Also particularly preferred are those inhalable powders wherein the 10% fine particle content is about 1 to 4 μm, preferably about 1.5 to 3 μm. The inhalable powders according to the invention are characterized, according to the problem on which the invention is based, by a high degree of homogeneity in the sense of the precision of the individual doses. This is the area <; 8%, preferably < 6%, more preferably < 4%. After weighing the starting materials, the inhalable powders are prepared from the excipient and the active substance, using methods known in the art. For example, reference can be made to the description of WO 02/30390. Accordingly, the inhalable powders according to the invention can be obtained, for example, by the method described below. In the preparation methods described below, the components are used in the proportions by weight described in the aforementioned inhalable powder compositions. First, the excipient and the active substance are placed in a suitable mixing container. The active substance used has an average particle size of 0.5 to 10 μm, preferably 1 to 6 μm, more preferably 2 to 5 μm. The excipient and the active substance are preferably added using a screen or a granulation screen with a mesh size of 0.1 to 2 mm, preferably 0.3 to 1 mm, more preferably 0.3 to 0.6 mm. Preferably, the excipient is added first and then the active substance is added to the mixing vessel. During the mixing process, the two components are preferably added in batches. It is particularly preferred to sift the two components in alternating layers. The mixing of the excipient with the active substance can occur while the two components are still being added. Preferably, however, mixing is only carried out once the two components have been sieved layer by layer. The present invention also relates to the use of the inhalable powders according to the invention for preparing a pharmaceutical composition for the treatment of severe persistent asthma as specified hereinabove. Inhalable powders according to the invention can be administered, for example, using inhalers that dose a single dose from a reservoir via a measuring chamber (eg, according to US 4570630A) or by other means (e.g. eg, according to DE 36 25 685 A). Preferably, however, the inhalable powders according to the invention are packaged in capsules (for making so-called capsules for inhalation), which are used in inhalers such as those described, for example, in WO 94/28958. More preferably, the capsules containing the inhalable powder according to the invention are administered using an inhaler as shown, for example, in Figure 1 of WO 03/084502 A1, which is incorporated herein by reference. This inhaler is characterized by a housing 1 containing two windows 2, a platform 3 in which there are air inlet openings and which is provided with a filter 5 fixed by a filter housing 4, an inhalation chamber 6 connected to the platform 3 in which there is a pusher 9 provided with two sharp pins 7 and movable in the opposite direction to a spring 8, and a nozzle 12 which is connected to the housing 1, the platform 3 and to a cover 11 by means of a spindle 10 to allow that opens or closes suddenly, as well as air intakes 13 to adjust the resistance of the flow. In order to administer the inhalable powders containing the crystalline tiotropium bromide forms according to the invention using powder-filled capsules, it is particularly preferred to use capsules whose material is selected from synthetic plastics, more preferably from polyethylene, polycarbonate, polyester, polypropylene and poly (ethylene terephthalate). Particularly preferred synthetic plastic materials are polyethylene, polycarbonate or poly (ethylene terephthalate). If polyethylene is used as one of the particularly preferred capsule materials according to the invention, it is preferable to use polyethylene with a density between 900 and 1000 kg / m3., preferably 940-980 kg / m3, more preferably about 960-970 kg / m3 (high density polyethylene). The synthetic plastics according to the invention can be processed in various ways, using preparation methods known in the art. The injection molding of the plastics according to the invention is preferred. For molding, injection molding is especially preferred without the use of release agents. This production method is well defined and is characterized by being particularly reproducible. In another aspect, the present invention relates to the aforementioned capsules containing the aforementioned inhalable powder according to the invention. These capsules may contain about 1 to 20 mg, preferably about 3 to 15 mg, more preferably about 4 to 12 mg of inhalable powder. In accordance with the invention, formulations containing 4 to 6 mg of inhalable powder are preferred. Of equal importance according to the invention are capsules for inhalation containing the formulations according to the invention in an amount of 8 to 12 mg. The present invention also relates to the use of the capsules mentioned above, characterized by an inhalable powder content according to the invention, for preparing a pharmaceutical composition intended to treat moderate persistent asthma as specified hereinabove. The filled capsules containing the inhalable powders according to the invention are produced by methods known in the art, by filling the empty capsules with the inhalable powders according to the invention. Examples of inhalable powders The following Examples serve to illustrate the present invention in more detail without restricting the scope of the invention to the following exemplary embodiments. The examples mentioned indicate the amount of active ingredient in a powder mixture of 5.5 mg. A person skilled in the art can prepare higher amounts of powder based on the concentration provided in the formulations exemplified below. In addition to the active ingredient, the mixture contains only the indicated excipient. The examples mentioned can be introduced into capsules for inhalation with appropriate inhalers. Alternatively, the mentioned examples can be used with multi-dose dry powder inhalers (MDPI). These MDPI contain the powder in the form of previously measured doses or deposits not previously measured. Appropriate devices are known in the art. Formulation Example 1: Tiotropium bromide monohydrate: 0.225 mg Lactose monohydrate: up to 5.5 mg Formulation example 2: Tiotropium bromide: 0.0226 mg Lactose monohydrate: up to 5.5 mg Formulation example 3: Non-hydrated tiotropium bromide: 0.0225 mg Lactose monohydrate : up to 5.5 mg Formulation example 4: Non-hydrated tiotropium bromide: 0.0111 mg Lactose monohydrate: up to 5.5 mg Formulation example 5: Non-hydrated tiotropium bromide: 0.0226 mg Lactose monohydrate: * up to 5.5 mg *) Lactose contains 5% of specifically added fine content of micronized lactose monohydrate with an average particle size of about 4 μm. Formulation Example 6: Tiotropium Bromide Monohydrate: 0.0225 mg Lactose monohydrate: * up to 5.5 mg *) Lactose contains 5% specifically added fine content of micronized lactose monohydrate with an average particle size of about 4 μm. Formulation Example 7: Non-hydrated tiotropium bromide: 0.0112 mg Lactose monohydrate: * up to 5.5 mg *) Lactose contains 5% specifically added fine content of micronized lactose monohydrate with an average particle size of about 4 μm. Aerosol suspensions containing propellant The tiotropium salt can also be optionally administered in the form of inhalable aerosols containing propellant. Aerosol suspensions are particularly suitable for this. The present invention also relates, therefore, to suspensions of the crystalline forms of tiotropium bromide according to the invention in the propellant gases HFA 227 and / or HFA 134a, optionally combined with one or more other propellant gases, preferably selected from the group consisting of in propane, butane, pentane, dimethyl ether, CHCIF2, CH2F2, CF3CH3, isobutane, isopentane and neopentane. According to the invention, those suspensions containing as propellant only HFA 227, a mixture of HFA 227 and HFA 134a or only HFA 134a are preferred. If a mixture of propellant gases HFA 227 and HFA is used 134a in the suspension formulations according to the invention, the weight ratios in which these two propellant gas components are used will vary freely. If one or more other propellant gases are used, selected from the group consisting of propane, butane, pentane, dimethyl ether, CHCIF2, CH2F2, CF3CH3? isobutane, isopentane and neopentane in addition to the propellant gases HFA 227 and / or HFA 134a in the suspension formulations according to the invention, the amount of this additional propellant component is preferably less than 50%, preferably less than 40%, particularly less than 30%. The suspensions according to the invention preferably contain a form amount of tiotropium bromide such that the amount of tiotropium cation is between 0.001 and 0.8%, preferably between 0.08 and 0.5%, and especially preferably between 0.2 and 0.4% of according to the invention. The percentages expressed within the scope of the present invention are always percentages by weight, unless otherwise specified. In some cases, the term suspension formulation is used within the scope of the present invention in place of the term suspension. The two terms will be considered equivalent within the scope of the present invention. The inhalable aerosols containing propellant or the suspension formulations according to the invention may also contain other constituents such as surface active agents (surfactants), adjuvants, antioxidants or flavorings. The surface active agents (surfactants) optionally present in the suspensions according to the invention are preferably selected from the group consisting of Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08, isopropyl myristate, oleic acid, propylene glycol, polyethylene glycol, Brij, ethyl oleate, glyceryl trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monostearate, glyceryl monorricinoleate, cetyl alcohol, stearyl alcohol, cetylpyridinium chloride, block polymers, natural oil, ethanol and isopropanol . Of the suspension adjuvants mentioned above, Polysorbate 20, Polysorbate 80, is preferably used, Myvacet 9-45, Myvacet 9-08 or isopropyl myristate. More preferably, Myvacet 9-45 or isopropyl myristate are used. If the suspensions according to the invention contain surfactants, these are preferably used in an amount of 0.0005-1%, particularly preferably 0.005-0.5%. Adjuvants optionally contained in the suspensions according to the invention are preferably selected from the group consisting of alanine, albumin, ascorbic acid, aspartame, betaine, cysteine, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid and citric acid. Preferably, ascorbic acid, phosphoric acid, hydrochloric acid or citric acid are used, although hydrochloric acid or citric acid is more preferably used. If adjuvants are present in the suspensions according to the invention, they are preferably used in an amount of 0.0001-1.0%, preferably 0.0005-0.1%, particularly preferably 0. 001-0.01%, while an amount of 0.001-0.005% is particularly important according to the invention. The antioxidants optionally contained in the suspensions according to the invention are preferably selected from the group consisting of ascorbic acid, citric acid, sodium edetate, editic acid, tocopherols, butylhydroxytoluene, butylhydroxyanisole and ascorbyl palmitate, while preferably tocopherols are used, butylhydroxytoluene, butylhydroxyanisole or ascorbyl palmitate. The flavors optionally contained in the suspensions according to the invention are preferably selected from the group consisting of peppermint, saccharin, Dentomint, aspartame and ethereal oils (for example cinnamon, anise seed, menthol, camphor) of which peppermint or Dentomint® is particularly preferred. With respect to administration by inhalation it is essential to provide the active substances in finely divided form. For this purpose, the crystalline tiotropium bromide forms according to the invention are obtained in finely divided form using methods known in the prior art. Methods for micronizing active substances are known in the art. Preferably after micronising the active substance has an average particle size of 0.5 to 10 μm, preferably 1 to 6 μm, particularly preferably 1.5 to 5 μm. Preferably at least 50%, preferably at least 60%, particularly preferably at least 70% of the particles of active substance have a particle size which is within the size ranges mentioned above. Preferably at least 80%, more preferably at least 90% of the particles of active substance have a particle size which is within the aforementioned size ranges. In another aspect, the present invention relates to suspensions containing only one of the two active substances according to the invention without any other additive.

Suspensions according to the invention can be prepared using methods known in the art. For this, the constituents of the formulation are mixed with the propellant gas or gases (optionally at low temperatures) and loaded in suitable containers. The aforementioned propellant containing suspensions according to the invention can be administered using inhalers known in the art (MDIp = pressurized metered dose inhalers). Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of suspensions, as previously described herein, combined with one or more inhalers suitable for administering these suspensions. In addition, the present invention relates to inhalers that are characterized in that they contain the suspensions containing the propellant described above according to the invention. The present invention also relates to containers (cartridges) which when equipped with a suitable valve can be used in a suitable inhaler and which contain one of the above-mentioned propellant-containing suspensions according to the invention. Containers (cartridges) and suitable methods for loading said cartridges with the suspensions containing propellant are known in the art. In view of the pharmaceutical activity of tiotropium, the present invention further relates to the use of suspensions according to the invention for preparing a pharmaceutical composition for inhalation or nasal administration, preferably for preparing a pharmaceutical composition intended for the treatment by inhalation or nasal diseases. wherein anticholinergics may have a therapeutic benefit.

In a particularly preferred manner, the present invention also relates to the use of the suspensions according to the invention for preparing a pharmaceutical composition intended for the treatment by inhalation of moderate persistent asthma as specified hereinabove. The following Examples serve to illustrate the present invention in more detail, by way of example, without limiting it to its contents. Examples of aerosol suspension formulations Suspensions containing other ingredients in addition to the active substance and the propellant gas: Formulation example 8: Constituents Concentration [% w / w] tiotropium bromide monohydrate 0.08 oleic acid 0.005 HFA -227 to 100 Eiemc > Formulation 9: Constituents Concentration [% w / w] tiotropium bromide monohydrate 0.04 oleic acid 0.01 HFA -227 60.00 HFA-134a up to 100 Example of formulation 10: Constituents Concentration [% w / w] tiotropium bromide monohydrate 0.04 isopropyl myristate 1.00 Formulation example 11: Formulation example 12 Formulation Example 13: Formulation Example 14: Formulation Example 15: Formulation Example 16: Formulation example 17: Formulation example 18: Formulation example 19: Formulation Example 20: Formulation Example 21: Formulation example 22: Aerosol formulations without propellant It is particularly preferred to use the tiotropium salts according to the invention to prepare inhalable solutions and suspensions without propellant. The solvent used can be an aqueous or alcoholic solution, preferably an ethanolic solution. The solvent can be the water itself or a mixture of water and ethanol. The relative proportion of ethanol compared to water is not limited, but the maximum is up to 70 volume percent, more particularly up to 60 volume percent and more preferably up to 30 volume percent. The rest of the volume is water. The solutions or suspensions containing 1 are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. More preferably, the pH of the formulation is between 2.8 and 3.05, preferably between 2.85 and 3.0, and more preferably is 2.9. The pH can be adjusted using acids selected from inorganic or organic acids. Examples of especially suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, melic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid etc. The preferred inorganic acids are hydrochloric and sulfuric acids. It is also possible to use acids that have already formed a salt by adding acids with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids can be used, especially in the case of acids having other properties besides their acidifying qualities, for example as flavorings, antioxidants or complexing agents, such as, for example, citric acid or ascorbic acid . According to the invention, the use of hydrochloric acid to adjust the pH is especially preferred. According to the invention, the addition of editic acid (EDTA) or one of its known salts, sodium edetate, as a stabilizer or complexing agent in the present formulation is not necessary. Other embodiments may contain this compound or these compounds. In a preferred embodiment, the content, based on sodium edetate, is less than 100 mg / 100 ml, preferably less than 50 mg / 100 ml, more preferably less than 20 mg / 100 ml. Generally, inhalable solutions are preferred in which the sodium edetate content is from 0 to 10 mg / 100 ml. Inhalable solutions which can be used according to the invention can be added cosolvents and / or other excipients. Preferred co-solvents are those containing hydroxyl groups or other polar groups, for example alcohols (especially isopropyl alcohol, glycols) especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene esters of fatty acids. The terms excipients and additives in this context indicate any pharmaceutically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in the suitable solvent from a pharmacological point of view in order to improve the qualitative properties of the formulation of the active substance. Preferably, these substances do not have a pharmacological effect or, with respect to the desired therapy, do not have an appreciable or at least undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives which guarantee or prolong the duration at room temperature of the final pharmaceutical formulation, flavors, vitamins and / or other additives known in the art. The additives also include pharmaceutically acceptable salts such as sodium chloride as isotonic agents. Preferred excipients include antioxidants such as, for example, ascorbic acid provided it has not previously been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins and provitamins found in the human body. Preservatives may be used to protect the formulation against contamination with pathogens. Suitable preservatives are those known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate. Of particular importance is benzalkonium chloride at concentrations up to 50 mg / 100 ml, more preferably between 5 and 20 mg / 100 ml, even more preferably 8-15 mg / 100 ml of the formulation. Preferred formulations contain, in addition to the solvent, water and the salts of tiotropium 1, only benzalkonium chloride and sodium edetate. In another preferred embodiment, sodium edetate is not present. Non-propellant non-removable solutions that can be used within the scope of the invention are in particular administered using inhalers of the type that are capable of nebulizing a small amount of a liquid formulation at the therapeutic dose in a few seconds to produce an aerosol suitable for inhalation. therapy. Within the scope of the present invention, preferred inhalers are those in which an amount of less than 100 μl, preferably less than 50 μl, more preferably between 10 and 30 μl of the solution of the active substance may be nebulized preferably in a spray to form an aerosol with an average particle size of less than 20 μm, preferably less than 10 μm, so that the inhalable part of the aerosol corresponds to the therapeutic effective amount. Such an apparatus for administration without propellant of a measured amount of a liquid pharmaceutical composition for inhalation is described, for example, in International Patent Application WO 91/14468 and also in WO 97/12687 (compare, in particular, Figures 6a and 6b). The nebulizers (devices) described in these references are also known by the name Respimat®. The concentration of the tiotropium salt based on the proportion of tiotropium in the finished pharmaceutical preparation depends on the therapeutic effect to be achieved. For most conditions that respond to tiotropium, the concentration of tiotropium is between 0.01 g per 100 ml of formulation and 0.06 g per 100 ml of formulation. An amount of 0.015 g / 100 ml to 0.055 g / 100 ml is preferred, and an amount of 0.02 g / 100 ml to 0.05 g / 100 ml is more preferred. An amount of 0.023 + 0.001 g per 100 ml of formulation up to 0.045 + 0.001 g per 100 ml of formulation is more preferred in the present invention. Examples of aerosol formulations without propellant 100 ml of pharmaceutical preparation contain: * the specified amount refers to the tiotropium cation as an active entity of tiotropium bromide; 1 mg of tiotropium corresponds to 1.2494 mg of tiotropium bromide monohydrate. The rest of the formulations 23-28 is purified water or water for injection at a density of 1.00 g / cm3 at a temperature of 15 ° C to 31 ° C.

If the formulations mentioned above in this document are supplied with the Respimat device, 2 device performances provide 22.1 μl of the formulation. Therefore, two performances of the device release, with the formulations according to examples 23, 25 and 27, a dose of 5 μg of tiotropium (with respect to the calculation for the cation). Two actions of the device release, with the formulations according to examples 24, 26 and 28, a dose of 10 μg of tiotropium (with respect to the calculation for the cation). Depending on the patient's condition, 3 or 4 actions can also be administered. Examples 33 to 42 additional: Analogs to examples 23 to 32, but with 8 mg of sodium edetate. Examples 43 to 52 additional: Analogs to examples 23 to 32, but with 12 mg of sodium edetate. Examples 53 to 62 additional: Analogs to examples 23 to 32, but with 8 mg of benzalkonium chloride. Examples 63 to 72 additional: Analogs to examples 23 to 32, but with 12 mg of benzalkonium chloride. From Examples 23 to 32, formulations 23 to 28 are of particular interest, Formulation Examples 23-24 being of the greatest importance.

Claims (10)

1. CLAIMS 1.- Use of tiotropium salts wherein X "indicates an anion with a single negative charge, preferably an anion selected from chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate, optionally in the form of the hydrates and / or solvates thereof, for the preparation of a medicament for the treatment of moderate persistent asthma
2. 2. Use according to claim 1, for the treatment of patients who 3. They have asthma in stage 3 of severity of GINA
3. 3. Use according to claim 1 or 2, for the preparation of a medicament for the treatment of moderate persistent asthma in patients who show daily symptoms despite treatment with corticosteroids
4. 4. Use according to claim 1 or 2, for the preparation of a medicament for the treatment of moderate persistent asthma in patients with persistent symptoms. In spite of treatment with inhaled beta-2-agonists in patients carrying the Arg / Arg genotype in codon 16 of the ADRB2 gene (chromosome 5).
5. 5. Use according to claim 1 or 2, for the preparation of a medicament for the treatment of moderate persistent asthma in patients carrying the Arg / Arg genotype in codon 16 of the ADRB2 gene (chromosome 5) who present daily symptoms despite of combined treatment with corticosteroids and long-acting inhaled beta-2-agonists.
6. 6. Use according to one of claims 1 to 5, for the preparation of a medicament for the treatment of moderate persistent asthma, in which the patients are children.
7. 7. Use according to one of claims 1 to 6, for the preparation of a medicament for the maintenance treatment of moderate persistent asthma and the prevention of broncho-obstructive symptoms in patients who are not adequately controlled by the treatment of maintenance control with inhaled corticosteroids and long-acting beta-2-agonists.
8. 8. Use according to one of claims 1 to 6, for the preparation of a medicament for the maintenance treatment of asthma in stage 3 of severity of GINA and the prevention of broncho-obstructive symptoms in patients who are not adequately controlled by the maintenance control treatment with inhaled corticosteroids and long-acting beta-2-agonists.
9. 9. Use according to one of claims 1 to 6, for the preparation of a medicament for third line maintenance control therapy for the treatment of moderate persistent asthma.
10. 10. Use according to one of claims 1 to 9, wherein for each individual dose, preferably 1 to 20 μg of tiotropium Y is administered.