AU2012258410B2 - Use of tiotropium salts in the treatment of severe persistant asthma - Google Patents

Abstract

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

Description

Australian Patents Act 1990 - Regulation 3.2A ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title "Use of tiotropium salts in the treatment of severe persistant asthma" The following statement is a full description of this invention, including the best method of performing it known to us: C \NRPob\DCC\ACGM770934_ ,DOC -27/]1/12 USE OF TIOTROPIUM SALTS IN THE TREATMENT OF SEVERE PERSISTENT ASTHMA ]This is a divisional of Australian Patent Application No. 2006277968, the entire contents 'ofwhich are incorporated herein by reference. The instant invention relates to the use of tiotropium salts for the manufacture of a 5 medicament for the treatment of patients suffering from severe persistent asthma. Background of the invention Asthma is one of the most common chronic diseases worldwide. It is a chronic inflammatory disorder of the airways. Asthma causes recurring episodes of wheezing, 10 chest tightness, breathlessness, and coughing. Asthma attacks (or exacerbations) are episodic, but airway inflammation is chronically present. Asthma is known to occur in different severity. Asthma severity can be intermittent, or it can be persistently mild, moderate or severe. Severity varies among individuals, does not necessarily relate to the frequency or persistence of symptoms, and can change in one individual over time. 15 Treatment decisions are made based on severity and vice versa, the severity classification level is based on the medication therapy. According to worldwide accepted guidelines of GINA (Global initiative for asthma) asthma severity can be classified into so called GINA steps I to 4. The severity of asthma 20 determines the treatment to be required (see hereto: GINA - Pocket guide for asthma management and prevention as updated 2004). For many patients, medication must be taken every day to control symptoms, to improve lung function and to prevent attacks. Medications are optionally also required to relieve acute symptoms such as wheezing, chest tightness, and cough. 25 GINA step I asthma is also called interinittent asthma. Symptoms occur usually less than one per week. GINA step I asthma does usually not require daily medication. In mild persistent asthma (GINA step 2) the recommended medication is treatment with low-dose inhaled corticosteroids. For moderate persistent asthma (GINA step 3) 30 administration of low to medium dose corticosteroids in combination with long-acting inhaled beta-2-agonists is recommended. Finally, severe persistent asthma (GINA step 4) is usually treated with high-dose inhaled corticosteroids in combination with long acting inhaled beta-2-agonists plus one or more of the following if needed: sustained release theophylline, Icukotriene modifier, long-acting 35 oral beta-2-agonist, and oral conticosteroids.

In an aspect the invention provides for an alternative ireatnieni of patients suFfering From severe persistent astiia. The invention also provides for suilable pharmaceutical compositions for the treatment ofthese4 patients. lDescri plion of the invent ion lie instant invention relates to the use oF tiotropium salts 1. for the manuI1h faciture of a medicalllent for the treatment of patients suffering from severe persistent asthma. The compound (iotropiuim bromide is known from European Patent Applicabton EP 418 716 10 A I and has the chemical structure: + Me Me-.N 0 H X 3 0 OH Wherein X denotes bromide. Within the scope of the present invention the term tiOropiul should be taken as being a reference to the free cation 1'. 15 By the tiotropiunm salts I which mty be used within the scope ol' the present invention are meant the compounds which contain. in addition to tiotropitur ' as counter-ion an anion X with a single nCgative charge, pre ferably an anion which is selected Imm among chloride. bromide, iodide, sulphate. phosphate. methanesul phonatc. nitrate. maleate. acetate. c ittC. fumarate. tarirate, oxalate. SUCc inate. beizoate and p-toluenesulphonate contain. while the 20 chloride, bromide, iodide, sulphate, nithanesuiph onate or p-tolunenesul phonate are pre ferred as Counter-ions. OFall tle salts tle chloride. bromide. iodide and methanesuIlholate are particularly prefIrred. Tiotropium bromide is ofoutstanding importance according to the invention. preferably in form of the crystalline tiotropium bromide monohydrate which is disclosed in WO 02/30928. In another preferred enbodiment anhydrous tiotropiui bromide 25 as disclosed in WO 03/000265 or in WO 05/042527 is used within the scope ol the i 1Vention. I rom these two anhydroiis lorns the one di se closed in W0 05,042527 is of part ic tiltr' in tere st.

Within the scope of the invention the term severe persistent asthma is to be understood as asthma with the severity GINA step 4. Asthma in the severity GINA step 4 is characterised by continuous symptoms, frequent exacerbations, frequent night-time symptoms, limited physical activity of the patient despite the available controller medication (e.g. inhaled 5 corticosteroids and long-acting beta-2-agonists) or PEF and FEVI-values < 60% with a PEF variability of >30%. According to the GINA guidelines the presence of only one of these features of severity is sufficient to place a patient in that category. PIEF (peak expiratory flow) values can be measured with peak flow meters known in the art. Spirometers known in the art are used to measure the so called forced expiratory 10 volume in I second (FEV,). The methods for determination of PEF and FEVI are well established in the art. The invention also relates to the use of tiotropium salts I for the manufacture of a medicament for the treatment of patients suffering from asthma in the severity GINA step 15 4. The invention also relates to the use of tiotropium salts I for the manufacture of a medicament for the treatment of asthma in patients suffering from continuous symptoms. The invention also relates to the use of tiotropium salts 1 for the manufacture of a medicament for the treatment of asthma in patients suffering from frequent exacerbations. The invention also relates to the use of tiotropium salts I for the manufacture of a 20 medicament for the treatment of asthma in patients suffering from frequent night symptoms. The invention also relates to the use of tiotropium salts I for the manufacture of a medicament for the treatment of asthma in patients with limited physical activity. The invention also relates to the use of tiotropium salts I for the manufacture of a medicament for the treatment of asthma in patients with PEF -values <60%. The invention also relates 25 to the use of tiotropium salts I for the manufacture of a medicament for the treatment of asthma in patients with FEVI-values < 60%. The invention also relates to the use of tiotropium saltS for the manufacture of a medicament for the treatment of asthma in patients with a PEF variability of >30%, 30 Furthermore, the instant invention relates a method for the treatment of patients suffering from severe persistent asthma, 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 in the severity GINA step 4, comprising the administration of a therapeutically effective amount of a tiotropium salt I The invention also relates to a -3method for the treatment of patients suffering from asthma with continuous symptoms, comprising the administration of a therapeutically effective amount of a tiotropiurn salh 1. The invention also relates to a method for the treatment of patients suffering from asthma S 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 suffering from asthma with frequent night-symptoms, comprising 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 limited physical 10 activity, comprising the administration of a therapeutically effective amount of a tiotropium salt I. The invention also relates to a method for the treatment of asthma in patients with PEF -values < 60%, comprising the administration of a therapeutically effective amount of a iotropium salt 1. The invention also relates to a method for the treatment of asthma in patients with FEVI-values 5 60%, comprising the administration of 15 a therapeutically effective amount of a tiotropium salt 1. The invention also rClates to a method for the treatment of asthma in patients with a PEF variability of >30%, comprising the administration of a therapeutically effective amount of a tiotropium salt 1. The term "therapeutically effective amount" shall mean that amount of a drug or 20 pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician. For severe and persistent asthma medical treatment with corticostcroids is recommended. However, patients suffering from severe persistent asthma do often show persistent 25 symptoms despite of a treatment with inhaled corticosteroids. In another embodiment the invention, therefore, relates to the use of tiotropium salts I for the manufacture of a medicament for the treatment of severe persistent asthma in patients showing persistent symptoms despite of treatment with inhaled corticosteroids. 30 For severe and persistent asthma medical treatment with beta-2-agonists, in particular with inhaled long-acting beta-2-agonists is also recommended. However, patients suffering from severe persistent asthma do often show persistent symptoms despite of a treatment with inhaled beta-2-agonists. In another embodiment the invention, therefore, relates to the use of tiotropium salts 1 for the manufacture of a medicament for the treatment of severe -4persistent asthma in patients showing persistent syiptonis despite of treatment with inhaled beta-2-agonists. For severe and pcrs:sienl asthma medical treatment whih coticosieroids i) combination with 5 long-acting beta-2-agunists is recommended as primary controller therapy. however, patients suffering kfom severe persistent asthma do often show persistent asthma symptoms despite of a treatment with inhaled corticosteroids in combination with long-acting beta-2-agonists. In another embodiment the invention, therefore. relates to the [ISe oftiotropium salts I lor the nanolacoure uf a medicament lor the treatment ol severe pCrsistent asthma inl patinilS 10 showing persistent symptoms despite of combined treatment with inhaled corticosteroids and long-acting beta-2-ogonists. In a vet another preferred embodiment. the invention relates to the use of iotropium salts 1 for the Imanufacturie of a medieaient for the maintenance treatment ot severe persisteilt is asthma and the prevention of broneho-obstructive symptoms in patients who re not adequatch contro lled by maincnalnce controller treatment with inhaled corticosicroids and long-acting beta-2-agonists. In a yet another preferred embodiment, the invention relates to the use of tiotropiun salts 20 1 for the manufacture of a medicament for the maintenance treatment of asthma in the severity GINA step 4 and the prevention of broncho-obstructive symptoms in patients who arc not adequately controlled by maintenanCC controller treatment with inhaled corticosteroidsand ong-uc ting betm-2-agonisis. 25 In a yet another preferred embodiment. the Invention relates to the use of liolropiuri n' salts _ for the manulacture of a medicament for the ird-line maintenance comroller therapy for die -Catlmeni of severe persislen t asdtima. In a yet another prefrrd eumbodimen the iWenrion relies to the uSc of tiOtropiumi Ar the 30 nanufature of a medicament for the maintenance treatment of severe persistent asth ma and the prevention of broncho-obstructive symptoms in patients who receive already maintenalcC controller treatment with inhaled court icosteroids and Ing-acting beta-2-agonists. -5in a yet another prelferred embodiment, the invention relates to a method fIr the maintenance treatment of'severe persistent asthma and the prevention of broncho-obstructive symptoms in a patient who receives already maintenance controLler treatment with inhaled coricosicroids and long-acting beta-2-agonists. said method comprising the administration S to said patio ent of a tiotropium salt I In another embodiment the invention provides use of tiotmpiumat salts 1 + Me 0 He N OH 10 wherein X denotes bromide, optionally in form of the hydrates and/or solvates thereof, in the m1anulaCture ofa medicament [or the maintenance treatment of severe persistent asthnia and the prevention of broncho-obstructive symptoms in patients who receiTve already maintenance controller treatment with inhaled corticosteroids and long-acting beta 2-agonists. In another embodiment the invention provides a method for the maintenance treatment of severe persistent asthma and the prevention of broncho-obstructive svmptonms in a Patient who receives already maintenance controller treatment with inhaled corticosteroids and long-acting beLa-2-agoaists. said method comprising the administration to said patient of a 20 liotropium Salt I + Me H so S -0 OH wherein X- denotes bromide, optionally in Form of the hydrates and/or sokates thereoF

-A-

In a yet another preferred embodiment, the invention relates to the use of tiotropium salts 1 for the manufacture of a medicament for the maintenance treatment of asthma in the severity GINA step 4 and the prevention of broncho-obstructive symptoms in patients who receive already maintenance controller treatment with inhaled corticosteroids and long 5 acting beta-2-agonists, In a yet another preferred embodiment, the invention relates to the use of tiotropiurn salts I for the manufacture of a medicament for the maintenance treatment of severe persistent asthma and the prevention of broncho-obstructive symptoms in patients who receive 10 already maintenance controller treatment with inhaled corticosteroids und long-acting beta 2-agonists, wherein the inhaled corticosteroid is selected from among prednisolone, prednisone, butixocortpropionate, RPR-106541, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, (S)-fluoromethyl 6cr,9ca-difluoro-17a-[(2-furanylcarbonyl)oxy]-1

]P

15 hydroxy- 16a-methyl-3-oxo-androsta- I,4-diene- I 70-carbothionate, (S)-(2-oxo-tetrahydro furan-3S-yl)6a,9a-difluoro- I-I hydroxy-I 6cc-methyl-3-ox6- I 7a-propionyloxy-androsta 1,4-dienc- I 70-carbothionate and etiprednol-dichloroacetate (BNP-166, ), optionally in the form of the racemates, enantiomers or diastercomers thereof and optionally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof. 20 In a yet another preferred embodiment, the invention relates to the use of tiotropium salts 1 for the manufacture of a medicament for the maintenance treatment of severe persistent asthma and the prevention of broncho-obstructive symptoms in patients who receive already maintenance controller treatment with inhaled corticosteroids and long-acting beta 25 2-agonists, wherein the inhaled corticosteroid is selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ST-126, dexamethasone, (S)-fluoromethyl 6a.9a-difluoro-17Q-((2 furanylcarbonyl)oxy] -i1-hydroxy-1 6a-methyl-3-oxo-androsta-1,4-diene-17f carbothionate, (S)-(2-oxo-tetrahydro-furan-3S-yl)6a,9a-diluoro- I I3-hydr oxy-16a 30 methyl-3-oxo-1 7a-propionyloxy-androsta- 1,4-diene- I 71-carbothionate and etiprednol dichloroacetate, optionally in the form of the racemates, onantiomers or diastereomers thereof and optionally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof. -6- In a yet another preferred embodiment, the invention relates to the use of tiotropium salts I for the manufacture of a medicament for the maintenance treatment of severe persistent asthma and the prevention of broncho-obstructive symptoms in patients who receive already maintenance controller treatment with inhaled corticosteroids and long-acting beta 5 2-agonists, wherein the inhaled corticosteroid is selected from among budesonide, fluticasone, mometasone, ciclesonide, (S)-fluoromethyl 6a,9Q-difluoro-17ct-((2 furanylcarbonyl)oxy]- II -hydroxy- 16Q-methyl-3-oxo-androsta- l,4-diene- 170 carbothionate and etiprednol-dichloroacetate, optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and derivatives i0 thereof, the solvates and/or hydrates thereof. Any reference to steroids includes a reference to any salts or derivatives, hydrates or solvates thereof which may exist. Examples of possible salts and derivatives of the steroids may be: alkali metal salts, such as for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, 15 pivalates or furoates. In a yet another preferred embodiment, the invention relates to the use of tiotropiurn salts I for the manufacture of a medicament for the maintenance treatment of severe persistent asthma and the prevention of broncho-obstructive symptoms in patients who receive 20 already maintenance controller treatment with inhaled corticosteroids and long-acting beta 2-agonists, wherein the long-acting beta-2-agonist is selected from among albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibutcrol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenalinc, pirbutcrol, procaterol, reproterol, TD 3327, ritodrine, 25 salmeterol, salmefamol, soterenot, sulphonterol, tiaramide, terbutaline, Eolubuterol, CH-r 4226 (= TA 2005 or carmoterol; ), HOKU-81, KUL-1248, 3-(4-{6-[2-Hydroxy-2-(4 hydroxy-3-hydroxymeth yl -phenyl)-eth ylamino)-hexyloxy) -butyl)-benzenesulfoneami de 5-[2-(5,6-Diethyl-indan-2-ylamino)-I-hydroxy-ethyl]-8-hydroxy- i-quinolin-2-one , 4 h ydroxy.-7-2- ([2- [ 3 -(2-phenylethoxy)propyl]sulphonyl Jethyl 1-amino) ethyl)-2(3H) 30 benzothi azolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-( -benzimidazolyl)-2-methyl-2 butylaminolethanol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyll-2-[4-(I benzimidazolyl)-2-methyl-2-butylamino~ethanol, 1 -[2H-5-hydroxy-3-oxo-4-I-,A benzoxazin-8-yl)- 2

-[

3 -(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, I (2H-5-hydroxy-3-oxo-4H-1, 4 -benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2 35 propylarninojethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-(3-(4-n -71 butyloxyphenyl)-2-methyl-2-propylaminojethanol, 1-[2H-5-hydroxy-3-oxo-4H--l,4 benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yll-2-methyl-2 butylamino}ethanol, 5-hydroxy-8-(I-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin 3-(4H),one, 1-(4-amino-3-chloro-5-trifluormethylphenyl)-2-tert.-butylamino)ethanol, J-(4 5 ethoxycarbonylamino-3-cyano-5~fluorophenyl)-2-(tert.-butylamino)ethanol, and N-[2 I-ydroxy-5-(I-hydroxy-2-(2-[4-(2-hydroxy-2-pheny-ethylamino)-phenyl-ecthylamino) ethyl)-phenyl]-formamide, optionally in the fonn of the racemates, the enantiomers, the diastereomers and optionally the pharmacologically acceptable acid addition salts and the hydrates thereof. 10 In a yet another preferred embodiment, the invention relates to the use of tiotropium salts 1 for the manufacture of a medicament for the maintenance treatment of severe persistent asthma and the prevention of broncho-obstructive symptoms in patients who receive already maintenance controller treatment with inhaled corticosteroids and long-acting beta 15 2-agonists, wherein the long-acting beta-2-agonist is selected from among bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formotero, hexoprenaline, ibuterol. pirbuterolt procaterol, reproterol, TD 3327, salmeterol, sulphonterol, terbutaline, tolubuterol, CHF 4226 (z TA 2005 or carmoterol; ). 3-(4- (6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymcthyl phenyl)-ethyl amino]-hexyloxy }-butyl)-benzenesulfoneamide, 5-[2-(5,6-Diethyl-indan-2 20 ylamino)- I -h ydroxy-eihyl]-8-h ydroxy- 1 -quinolin-2-one, 4-h ydroxy-7-[2- ([2-f [3-(2 phenylethoxy)propyllsulphonyl )ethyl]-amino) ethylj-2(3H)-benzothiazolone, 1-(2-fluoro 4-hydroxyphenyl)-2-[4-(I-benzimidazolyl)-2-methyl-2-butylaminojethanol, 1-[3-(4 methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(I -benziridazolyl)-2-methyl-2 butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N 25 dimethylaninophenyl)-2-methyl-2-propylaminolethanol, 1-[2H-5-hydrox y-3-oxo-41-1,4 benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-popylaminolethano 1-[21-1-5 hydroxy-3-oxo-41-11,4-benzoxazin-8-yl]-2~[3-(4-n-butyloxyphenyl)-2-methyl-2 propylamino]ethanol, I -[2H1-5-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 30 hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5 tri fluormethylphenyl)-2-tert.-butylamino)cthanol, I-(4-ethoxycarbonylamino-3-cyano-5 fluorophenyl)-2-(tert .-butylamino)ethanol, and N-(2-lydroxy-5-(I-hydroxy-2-{2-[4-(2 hydroxy-2-phcnyl-ethylamino)-phenyl]-ethylamino} -ethyl)-phenyl]- formamide, optionally in the form of the raccmates, the enantiomers, the diastercomers and optionally Ihe 35 pharmacologically acceptable acid addition salts and the hydrates thereof.

In a yet another preferred embodiment, the invention relates to the use of tiotropium salts 1 for the manufacture of a medicament for the maintenance treatment of severe persistent asthma and the prevention of broncho-obstructive symptoms in patients who receive 5 already maintenance controller treatment with inhaled corticosteroids and long-acting beta 2-agonists, wherein the long-acting beta-2-agonist is selected from among fenoterol, formoterol, salmeterol, CHF-4226 (= TA 2005 or carmoterol; ), 3-(4-{6-[2-Hydroxy-2-(4 hydrox y-3-hydroxymethyl-phenyl)-ethylamino]-hexylox y) -butyl)-benzenesulfoneamide 5-[2-(5,6-Diethyl-indan-2-ylamino)~i-hydroxy-ethyl]-8-hydroxy-III-quinolin-2-one, 1-[3 10 (4-methoxybenzyl-amino)-4-hydroxyphenylj-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 dimothylaminophcnyl)-2-mcthyl-2-propylamino]ethanol, I-[2H-5-hydroxy-3-oxo-4H-1,4 benzoxazin-8-yli-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 15 propylaminolethanol, 1-[2--5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2- 4-[3-(4 methoxyphenyl)- 1,2,4-tri azol-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) phonyl]-formamide, optionally in the form of the racemates, the enantiomers, the diastereomers and optionally the pharmacologically acceptable acid addition salts and the 20 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 hydroxymcthyl-phenyl)-ethylamino]-hexyloxy )-butyl)-benzenesulfoneamide, 5-[2-(5,6 Diethyl-indan-2-yl amino)- I -hydroxy-ethyl)-8-hydroxy- 1 H-quinolin-2-one are, and N-f2 Hydroxy-5-(1-hydroxy-2-{2-(4-(2-hydroxy-2-phenyl-cthylamino)-phenyl]-ethyl amino ) 25 ethyl)-phenyl)-formamide, particularly preferred, optionally in the form of the racemates, the enantiomers, the diastercomers and optionally the pharmacologically acceptable acid addition salts thereof, and the hydrates thereof. Examples of pharmacologically acceptable acid addition salts of the beta-2-agonist 30 according to the invention are the pharmaceutically acceptable salts which are selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuic acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1-hydroxy-2-naphthalenecarboxylic acid, 4-phenylcinnamic acid, 5-(2.4 difluorophenyl)salicylic acid or maleic acid. If desired, mixtures of the abovementioned 35 acids may also be used to prepare the salts . -9- According to the invention, the salts of the beta-2-agonist selected from among the hydrochloride, hydrobromide, sulphate, phosphate, fumarate, methancsulphonatc, 4 phenylcinnamate, 5-(2.4-difluorophenyl)salicylate, maleate and xinafoate are preferred. 5 Particularly preferred are the salts of in the case of salmeterol selected from among the hydrochloride, sulphate, 4-phenylcinnamate, 5-(2.4-di fluorophenyl)sal icyl ate and xinafoate, of which the 4-phenylcirnamate, 5-(2.4-di fluorophenyl)salicylate and especially xinafoate are particularly important. Particularly preferred are the salts of in the case of formoterol selected from the hydrochloride, sulphate, hemifumarate and fumarate, 10 of which the hydrochloride, hernifumarate and fumarate arc particularly preferred. Of exceptional importance according to the invention is formoterol fumarate dihydrate or formoterol hemifumarate hydrate. Any reference to the term beta-2-agonist also includes a reference to the relevant 15 enantiorners or mixtures thereof. In a yet another embodiment the invention, relates to the use of tiotropium salts I for the manufacture of a medicament for the treatment of severe persistent asthma wherein the patient are children, preferably children younger than 14, more preferably younger than 10. 20 even more preferably younger than 8, preferably younger than 6 years of age. In a particular preferred embodiment the children are younger than 5 years of age. In another aspect the present invention relates to the aforementioned use of tiotropium salts I wherein per each individual dose preferably I - 20 tg, more preferably 2 - 15 pg of 25 tiotropium ' are administered, In another aspect the present invention relates to the aforementioned use of tiotropium salts 1 wherein per each individual dose 5 - 10 ig of iotropium 1' are administered. In another aspect the present invention relates to the aforementioned use wherein the 30 tiotropium salts I are administered once, or twice, preferably once per day. In another aspect the present invention relates to the aforementioned use wherein the tiotropium sals 1 are administered in the morning or in the evening. Use of tiotropium salts 1 according to the invention includes the use of the solvates and 35 hydrates thus formed, preferably the hydrates, most preferably the monohydrates. -10- Based on the amounts of the active substance tiotropium ' administered per single dose as specified hereinbefore the skilled artisan may easily calculatethe corresponding amount of for instance tiotropiurn bromide and/or tiotropium bromide monohydrate. 5 The tiotropium salts 1 are preferably administered according to the invention by inhalation. For this purpose, the tiotropium salts I have to be prepared in inhalable forms. Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-frce inhalable solutions. Inhalable powders according to the invention i0 containing the tiotropium salts I optionally mixed with physiologically acceptable excipients, Within the scope of the present invention, the term propellant-frec inhalable solutions also includes concentrates or sterile inhalable solutions ready for use. The formulations which may be used within the scope of the present invention are described in more detail in the next part of the specification. 15 Inhalable powders which contain 0.01 to 2 % tiotropium are preferred according to the invention, Particularly preferred inhalable powders for use within the invention contain iotropium in an amount from about 0.03 to I %, preferably 0.05 to 0.6 %, particularly preferably 0.06 to 0.3 %. Of particular importance according to (he invention. finally, arc 20 inhalable powders which contain about 0.08 to 0.22 % tiotropium. The amounts of tiotropium specified above are based on the amount of tiotropium cation contained. The excipients that are used for the purposes of the present invention are prepared by 25 suitable grinding and/or screening using current methods known in the art. The excipients used according to the invention may also be mixtures of excipients which are obtained by mixing excipient fractions of different mean particle sizes. Examples of physiologically acceptable excipients which may be used to prepare the 30 inhalable powders for use in the inhalettes according to the invention include monosaccharides (e.g. glucose, fructose or arabinose), disaccharides (e.g. lactose, saccharose, maltose, trehalose), oligo- and polysaccharides (e.g. dextrans, dextrins, maltodextrin, starch, cellulose), polyalcohols (e.g. sorbitol, mannitol, xylitol), cyclodextrins (e.g. o-cyclodextrin, 0-cyclodextrin, X-cyclodextrin, methyl-1-cyclodextrin, 35 hydroxypropyl-0-cyclodextrin), amino acids (e.g. arginine hydrochloride) or salts (e.g. -1 sodium chloride, calcium carbonate), or mixtures thereof. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient. 5 Within the scope of the inhalable powders according to the invention the excipients have a maximum average particle size of up to 250sm, preferably between 10 and 150pm, most preferably between 15 and 80pm. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of I to 9ym to the excipients mentioned above. These finer excipients are also selected from the group of possible excipients listed 10 hereinbefore. The average particle size may be determined using methods known in the art (cf. for example WO 02/30389, paragraphs A and C). Finally, in order to prepare the inhalable powders according to the invention, micronised crystalline tiotropium bromide anhydrate, which is preferably characterised by an average particle size of 0.5 to 10pm, particularly preferably from 1 to 5ym, is added to the excipient mixture (cf. for example 15 WO 02/30389, paragraph B). Processes for grinding and micronising active substances are known from the prior art. If no specifically prepared excipient mixture is used as the excipicnt, it is particularly preferable to use excipients which have a mean particle size of 10 - 50 pm and a 10 % fine conent of 0.5 to 6 lm. 20 By average particle size is meant here the 50 % value of the volume distribution measured with a laser diffractometer using the dry dispersion method. The average particle size may be determined using methods known in the art (cf. for example WO 02/30389, paragraphs A and C). Analogously, the 10% fine content in this instance refers to the 10% value of the 25 volume distribution measured using a laser diffractometer. In other words, for Lhe purposes of the present invention, the 10% fine content denotes the particle size below which 10% of the quantity of particles is found (based on the volume distribution) The percentages given within the scope of the present invention are always percent by 30 weight, unless specifically stated to the contrary. In particularly preferred inhalable powders the excipient is characterised by a mean particle size of 12 to 35 pm, particularly preferably from 13 to 30 pm. -12- Also particularly preferred are those inhalable powders wherein the 10 % fine content is about I to 4 jim, preferably about 1.5 to 3 im. The inhalable powders according to the invention are charactcriscd, in accordance with the 5 problem on which the invention is based, by a high degree of homogeneity in the sense of the accuracy of single doses. This is in the region of < 8 %, preferably <6 %, most preferably <4 %. After the starting materials have been weighed out the inhalable powders are prepared 10 from the excipient and the active substance using methods known in the art. Reference may be made to the disclosure of WO 02/30390, for example. The inhalable powders according to the invention may accordingly be obtained by the method described below, for example, In the preparation methods described hereinafter the components are used in the proportions by weight described in the above-mentioned compositions of the inhalable 15 powders. 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 pm, preferably I to 6 jim, most preferably 2 to 5 jim. The excipient and the active substance are preferably added 20 using a sieve or a granulating sieve with a mesh size of 0.1 to 2 mm, preferably 0.3 to I mm, most preferably 0.3 to 0.6 mm. Preferably, the excipicnt is put in first and then the active substance is added to the mixing container. During this mixing process the two components are preferably added in batches. It is particularly preferred to sicve in the two components in alternate layers. The mixing of the excipient with the active substance may 25 take place while the two components are still being added, Preferably, however, mixing is only done once the two components have been sieved in layer by layer. The posent 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 30 asthma as specified hereinbefore, The inhalable powders according to the invention may for example be administered using inhalers which meter a single dose from a reservoir by means of a measuring chamber (e.g. according to US 4570630A) or by other means (e.g. according to DE 36 25 685 A). 35 Preferably, however, the inhalable powders according to the invention are packed into -13capsules (to make so-called inhalettes), which are used in inhalers such as those described in WO 94/28958, for example. Most preferably, the capsules containing the inhalable powder according to the invention 5 are administered using an inhaler as shown for instance in Figure 1 of WO 03/084502 Al, which is herby incorporated by reference. This inhaler is characterized by a housing I containing two windows 2, a deck 3 in which there are air inlet ports and which is provided with a screen 5 secured via a screen housing 4, an inhalation chamber 6 connected to the deck 3 on which there is a push button 9 provided with two sharpened pins 7 and movable 10 counter to a spring 8, and a mouthpiece 12 which is connected to the housing 1, the deck 3 and a cover II via a spindle JO to enable it to be flipped open or shut and airholcs 13 for adjusting the flow resistance. For administering the inhalable powders containing the crystalline tiotropium bromide i5 forms according to the invention using powder-filled capsules it is particularly preferred to use capsules the material of which is selected from among the synthetic plastics, most preferably selected front among polyethylene, polycarbonate, polyester, polypropylene and polyethylene terephthalate. Particularly preferred synthetic plastic materials are polyethylene, polycarbonate or polyethylene terephthalate. If polyethylene is used as one 20 of the capsule materials which is particularly preferred according to the invention, it is preferable to use polyethylene with a density of between 900 and 1000 kg/m , preferably 940 - 980 kg/m' more preferably about 960 - 970 kg/m (high density polyethylene); The synthetic plastics according to the invention may be processed in various ways using manufacturing methods known in the art. Injection moulding of the plastics is preferred 25 according to the invention. Injection moulding without the use of mould release agents is particularly preferred. This method of production is well defined and is charactcrised by being particularly reproducible. In another aspect the present invention relates to the abovementioned capsules which 30 contain the abovementioned inhalable powder according to the invention. These capsules may contain about I to 20 mg, preferably about 3 to 15 mg, most preferably about 4 to 12 mg of inhalable powder. Preferred formulations according to the invention contain 4 lo 6 mg of inhalable powder. Of equivalent importance according to the invention are capsules for inhalation which contain the formulations according to the invention in an 35 amount of from 8 to 12 mg. 14- The present invention also relates to the use of the abovementioned capsules characterized by a content of inhalable powder according to the invention, for preparing a pharmaceutical composition for treating of severe persistent asthma as specified 5 hereinbefore. Filled capsules which contain the inhalable powders according to the invention are produced by methods known in the an, by filling the empty capsules with the inhalable powders according to the invention. 10 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 exemplifying embodiments that follow. 15 The mentioned examples indicate the amount of active ingredient in a powder mixture of 5.5 mg. The person of ordinary skill in the art is able to prepare lager amounts of powder based on the concentration given in the formulations exemplified below, Besides the active ingredient the mixture contains only the indicated excipient. The mentioned examples can be filled into capsules for inhalation with appropriate inhalers. In 20 the alternative the mentioned examples can be used with multiple dose dry powder inhalers (MDPls). These MDPIs contain the powder in form of pre-metered doses or not pre metered, reservoirs. Appropriate devices are known in the an. Formulation Example 1: 25 tiotropium bromide monohydratc;0.0225 mg lactose monohydrate: ad 5.5 mg Formulation Example 2: 30 iotropium bromide: 0,0226 mg lactose monohydrate: ad 5.5 mg FormulatioqExample 3 35 tiolropium bromide anhydrate: 0.0225 mg lactose monohydrato: ad 5.5 mg Formulation Example 4; 5 tiotropiurn bromide anhydrate: 0.0111 mg lactose monohydrate: ad 5.5 mg Formulation Example 5; 10 tiotropium bromide anhydrate: 0.0226 mg lactose monohydrate:* ad 5.5 mg *) the lactose contains 5% specifically added fine content of micronised lactose monohydrate with a mean particle size of about 4pim. 15 Formulation Example 6; tiotropium bromide monohydrate:0.0225 mg lactose monohydrate;* ad 5.5 mg 20 *) the lactose contains 5% specifically added fine content of micronised lactose monohydrate with a mean particle size of about 4pm. Formulation Example 7: 25 tiotropium bromide anhydrate: 0.0112 mg lactose monohydrate:*l ad 5.5 mg *) the lactose contains 5% specifically added fine content of micronised lactose monohydrate with a mean particle size of about 4pm. 30 Propell an t-containing aerosol suspensions The tiotropium salt may optionally also be administered in the form of propellant containing inhalablc aerosols. Aerosol suspensions are particularly suitable for this. The present invention therefore also relates to suspensions of the crystalline tiotropium 35 bromide forms according to the invention in the propellent gases HFA 227 and/or HPA -16- 134a, optionally combined with one or more other propellent gases, preferably selected from the group consisting of propane, butane, pentane, dimethylether, CHCIF 2 , CI-1 2

F

2 ,

CFCH

3 isobutane, isopentane and neopentane. 5 According to the invention those suspensions which contain as propellent gas only HFA 227, a mixture of HFA 227 and HFA 134a or only HFA 134a are preferred. If a mixture of the propellent gases HFA 227 and HFA 134a is used in the suspension formulations according to the invention, the weight ratios in which these two propellent gas components are used are freely variable. 10 If one or more other propellent gases, selected from the group consisting of propane, butane, pentane, dimethylether, CHClF 2 , CH2F 2 , CFC-iisobutanc, isopentane and neopentane are used in addition to the propellent gases HFA 227 and/or HFA 134a in the suspension formulations according to the invention, the amount of this additional propellent gas component is preferably less than 50 %, preferably less than 40%, IS particularly preferably less than 30%. The suspensions according to the invention preferably contain an amount of tiotropium bromide form such that the amount of tiotropium cation is between 0.001 and 0.8%, preferably between 0.08 and 0.5%, and particularly preferably between 0.2 and 0.4% 20 according to the invention. Unless stated to the contrary, the percentages given within the scope of the present invention are always percent by weight. In some cases, the term suspension formulation is used within the scope of the present 25 invention instead of the term suspension. The two terms are to be regarded as equivalent within the scope of the present invention, The propellant-containing inhalable aerosols or suspension formulations according to the invention may also contain other constituents such as surface-active agents (surfactants), 30 adjuvants, antioxidants or flavourings. 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 myristatc. oleic acid, 35 propyleneglycol, polyethyleneglycol, Brij, ethyl oleate, glyceryl trioleate, glyceryl -17monolaurate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyLalcohol, sterylalcohol, cetylpyridinium chloride, block polymers, natural oil, ethanol and isopropanol. Of the above-mentioned suspension adjuvants Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08 or isopropyl myristate are preferably used. 5 Myvacet 9-45 or isopropyl myristate are most preferably used. If the suspensions according to the invention contain surfactants these are preferably used in an amount of 0.0005 - I %, particularly preferably 0.005 - 0.5 %. 10 The 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, sulphuric acid and citric acid. Ascorbic acid, phosphoric acid, hydrochloric acid or citric acid are preferably used, while hydrochloric acid or citric acid is most preferably used, 15 If adjuvants are present in the suspensions according to the invention, these 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. 20 The antioxidants optionally comained 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, butylhydroxyanisol and ascorbylpalmitate, while tocopherols, butylhydroxytoluene, butylhydroxyanisol or ascorbylpalmitate are 25 preferably used. The flavourings optionally contained in the suspensions according to the invention are preferably selected from the group consisting of peppermint, saccharine, Dentomint, aspartame and ethereal oils (for example cinnamon, aniseed, menthol, camphor), of which 30 peppermint or Dentomint@ are particularly preferred. With a view 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 35 prior an. Methods of micronising active substances are known in the art. Preferably after -18rnicronising the active substance has a mean particle size of 0.5 to 10Jm, preferably I to 6pm, particularly preferably 1.5 to 5Am. 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. Particularly preferably at least 80%, most S preferably at least 90% of the particles of active substance have a particle size which is within the size ranges mentioned above. In another aspect the present invention relates to suspensions which contain only one of the two active substances according to the invention without any other additives. The suspensions according to the invention may be prepared using methods known in the art. For this, the constituents of the formulation are mixed with the propellent gas or gases (optionally at low temperatures) and filled into suitable containers, The above-montioned propellant-containing suspensions according to the invention may be administered using inhalers known in the art (pMDIs = pressurized metered dose inhalers). Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of suspensions as hereinbefore described combined with one or more inhalers suitable for administering these suspensions. Moreover the present invention 20 relates to inhalers, characterized in that they contain the propellant-containing suspensions according to the invention described hereinbefore. The present invention also relates to containers (cartridges) which when fitted with a suitable valve can be used in a suitable inhaler and which contain one of the above 25 mentioned propellant-containing suspensions according to the invention. Suitable containers (cartridges) and processes for filling these cartridges with the propellant containing suspensions according to the invention are known in the art, In view of the pharmaceutical activity of tiotropium the present invention also relates to the 30 use of the suspensions according to the invention for preparing a pharmaceutical composition for inhalation or nasal administration, preferably for preparing a pharmaceutical composition for inhalative or nasal treatment of diseases in which anticholinergics may develop a therapeutic benefit. 1 9- Particularly preferably the present invention also relates to the use of the suspensions according to the invention for preparing a pharmaceutical composition for the inhalative treatment of severe persistent asthma as specified hereinbefore. 5 The Examples that follow serve to illustrate the present invention in more detail, by way of example, without restricting it to their contents. Examples of aerosol suspension formulations 10 Suspensions containing other ingredients in addition to active substance and propellent gas: Formulation Example 8: constituents concentration [% w/w] tiotropium bromide anhydrate 0,08 oleic acid 0,005 HFA-227 ad 100 Formulatioq Example 9' constituents concentration {% w/w] tiotropium bromide anhydratc 0.04 oleic acid 0,01 HPA-227 60.00 HFA-134a ad 100 Formulation Example 10 20 constituents concentration [% w/w] tiotropium bromide anhydrate (.04 isopropylmyristate 1.00 HFA-227 ad 100 Formulation Example 11: -20constituents concentration [% w/w] tiotropium bromide anhydrate 0.04 Myvacet 9-45 0.3 HFA-227 ad 100 Formulation Example 12: constituents concentration [% w/w] tiotropium bromide anhydrate 0.04 Myvacet 9-45 0.1 HFA-227 60.00 HFA-134a ad 100 5 Formulation Example 13; constituents concentration [% w/w) tiotil'Pum bromide anhydrate 0.04 Polysorbate 80 0.04 __FA-227 ad 100 Formulation Example 14; 10 constituents concentration (% w/w] tiotropium bromide anhydraic 0,02 Polysorbate 20 0.20 HFA-227 ad 100 Formulation Example 15; constituents concentration [% w/w) tiotropium bromide anhydrate 0.04 Myvacet 9-08 01.00 H4FA-227 ad 100 -21- Formulation Exumple 16: constituents concentration [% w/w] tiotropium bromide anhydrate 0,04 isopropylmyristate 0,30 HFA-227 20.00 HFA-134a ad 100 5 Formulation Example 17; constituents concentration [% w/w) tiotropium bromide anhydrate 0.03 HFA-227 60.00 HFA-134a ad 100 Formulation Example 18: constituents concentration [% w/w] tiotropiurn bromide anhydrate 0.04 H-FA-227 ad 100 10 ForulA Example 19 constituents concentration (% w/w) tiotropium bromide anhydrate 0,04 IHFA-134a ad 100 Formulaion Example 20: constituents concentration [% w/w) tiotropium bromide monohydrate 0.04 HfFA-227 ad 100 -22- Formulation Example 21, constituents concentration [% w/w] tiotropium bromide monohydrate 0.04 HIFA-134a ad 100 Formulation Example 22 constituents concentration [% w/w) tiotropium bromide anhydrare 0.02 HFA-227 20.00 HFA-134a 79.98 Propellant-free aerosol formulations It is particularly preferred to use the tiotropium salts . according to the invention to 10 prepare propellant-free inhalable solutions and suspensions. The solvent used may be an aqueous or alcoholic, preferably an cthanolic solution. The solvent may be water on its own or a mixture of water and ethanol. The relative proportion of ethanol compared with water is not limited but the maximum is up to 70 percent by volume, more particularly up to 60 percent by volume and most preferably up to 30 percent by volume. The remainder 15 of the volume is made up of water. The solutions or suspensions containing I are adjusted to a p-I of 2 to 7, preferably 2 to 5, using suitable acids. More preferably the pHi of the formulation is between 2.8 and 3.05, preferably between 2,85 and 3.0, and most preferably 2.9. 20 The pH may be adjusted using acids selected from inorganic or organic acids. Exampics of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid, Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids 25 are hydrochloric and sulphuric acids. It is also possible to usc the acids which have already formed an acid addition salt 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 may be used, particularly in the case of acids which have other propenics in -23addition to their acidifying qualities, e.g. as flavorings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH. 5 According to the invention, the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as stabiliser or complexing agent is unnecessary in the present formulation. Other embodiments may contain this compound or these compounds. In a preferred embodiment the content based on sodium cdetate is less than 100mg/100mil, preferably less than 50mg/100 ml, more preferably less than 20mg/100 ml. Generally, io inhalable solutions in which the content of sodium eCeCRatC is from 0 to 10mg/I00ml are preferred. Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions which may be used according to the invention. Preferred co-solvents are those which 5 contain hydroxyl groups or other polar groups, c.g. alcohols - particularly isopropyl alcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active 20 substance or substances in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation. Preferably, these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya lecithin, olcic acid, sorbitan esters, such as polysorbates, 25 polyvinylpyrroli done, other stabilizers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents. 30 The prefenred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins and provitamins occurring in the human body. Preservatives may be used to protect the formulation from contamination with pathogens, 35 Suitable preservatives are those which are known in the art, particularly cetyl pyridiniurn -24chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate. O particular imporacnce is benzalkonium chloride in concentrations of up to 50mg/lOmt, more preferably between 5 and 20mg/100ml, even more preferably 8-15 mg/100ml of the formulation. 5 Preferred formulations contain, in addition to the solvent water and the tiotropium salts 1, only benzalkonium chloride and sodium edetate. In another preferred embodiment, no sodium edetate is present. 10 The propellant-free inhalable solutions which may be used within the scope of the invention are administered in particular using inhalers of the kind which are capable of nebulising a small amount of a liquid formulation in the therapeutic dose within a few seconds to produce an aerosol suitable for therapeutic inhalation. Within the scope of the present invention, preferred inhalers are those in which a quantity of less than 100tL. 15 preferably less than 50 L, more preferably between 10 and 30pL of active substance solution can be nebulised in preferably one spray action to form an aerosol with an average particle size of less than 20pm, preferably less than 10 pm, in such a way that the inhalable part of the aerosol corresponds to the therapeutically effective quantity. 20 An apparatus of this kind for propellant-free delivery of a metered quantity of a liquid pharmaceutical composition for inhalation is described for example in International Patent Application WO 91/14468 and also in WO 97/12687 (cf. in particular Figures 6a and 6b). The nebulisers (devices) described therein are also known by the name Respimat@. 25 The concentration of the tiotropium salt based on the proportion of tiotropium in the finished pharmaceutical preparation depends on the therapeutic effect sought. For most of the complaints which 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 mi to 0.055 g / 100 ml is preferred, an amount of from 0.02 g / 100 ml to 0.05 30 g / 100 ml is more preferred. Most preferred in the instant invention is an amount of from 0.023 + 0,01g per 100 ml of formulation up to 0.045 ±0.00 lg per 100 ml of formulation. -25examples of propellant-free aerosol formulations 100 ml of pharmaceutical preparation contain: Example tiotropium*I corresponds to Amount of Amount of pH, adjusted tiotropium benzalkonium disodium with 1CI monohydrate chloride edetate (IN) 23 22.624 mg 28.267 mg 10 mg 10rmg. 2.9 24 45.249 mg 56.534 mg - 0 mg l09mg 25 22.624 mg 28.267 mg 0 m 10mg 2,8 26 45.249 mg 56.534 mg 010 m 2.8 27 22.624 r 28.267 mg 10 ma 10 3.0 28 45.249 mg 56.534 mg 10 mg 10 mg 3.0 29 22.624 mg 28.267 m 10 mg 10 mg 2.7 30 45.249 mg 56.534 mg 10 mg 0 mg 2.7 31 22.624 mg 28.267 mg 10_mg_ _0 3.1 32 45.249 mg 5 6,53 4 mg 10mg 10m 3 *the amount specified refers to the tiotropium cation as the active entity of tiotropium 5 bromide; I mg tiotropium corresponds to 1.2494 mg tiotropium bromide monohydrate The remainder of the formulations 23-28 is purified water or water for injections at a density of 1.00 g/cm3 at a temperature of 15 0 C to 31 0 C. 10 If the formulations mentioned hereinbefore are delivered with the Respimat device 2 actuations of the device deliver 22.19Al of the formulation. Two actuations of the device, therefore, deliver with the formulations according to examples 23, 25, and 27 a dose of 5Ag tiotropium (based on calculation for cation). Two actuations of the device deliver with the formulations according to examples 24, 26, and 28 a dose of 10pg tiotropium (based on 15 calculation for cation). Depending on the condition of the patient, also 3 or 4 actuations may for instance be administered, 20 Further Examples 33 to 42: Analogous to Examples 23 to 32, but with 8 mg of sodium edetate. -26- Further Examples 43 to 52: Analogous to Examples 23 to 32. but with 12 mg oI' sodium cdotate. Further ExampICs 53 to 62: 5 Analogous to Examples 23 to 32. but with 8 mg of benalkonium chloride. FIriher Examples 63 to 72: Analogous to I xamples 23 to 32. but with 12 ng of benzalkonium chloride, 1 Of the Ixamples 23 to 32. Formulation 23 to 28 are of particular interest, with formulation examples 23-24 being of utmost importance. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known. is not. and should not be taken as an acknowledgment or It admission or any lI)i of Suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the tield of endeavour to which this specica(ion relates. Throughout this specification and the claims which Jbllow. unless the context requires 20 Iherwise. the word "comprise". and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but 101 the exclusion of any other integer or step or group of integers or steps. -27-

Claims (1)

1. 4-hyd roxyphenyl)-2- [4 -(1 -benzimidazolyl)-2-nethyl-2-butylamino] ethanol, 1-[3-(4 methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2 butylaminolethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-ylj-2-[3-(4-N,N dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, I -[2H-5-hydroxy-3-oxo-4H-1,4 5 benzoxazin-8 -yI ]-2- [3 -(4-rnethoxyphenyl)-2-methyl-2-propylamino]ethano 1, 1-[2H-5 hydroxy-3-oxo-4H-1,4-benzoxazin-8-ylj-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-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5 10 trifluormethylphenyl)-2-tert.-butylamino)ethanol, 1-(4-ethoxycarbonylamino-3-eyano-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. 15 11) A method according to any one of claims 7 to 10, wherein for each individual dose 1-20 sg of tiotropium 1 is administered. 12) A method according to claim 11, wherein for each individual dose 2-15 sg of 20 liotropium 1 is administered. 13) A use or method according to any one of claims 1 to 12 substantially as hereinbefore described. -31 -