Abstract:
Pharmaceutical compositions and kits comprising:  
     (a) a tiotropium salt; and  
     (b) a salmeterol salt having a solubility in water of 0.1 mg/mL or less,  
     processes for preparing them, and their use in the treatment of respiratory complaints, asthma, and chronic obstructive pulmonary disease (COPD).

Description:
[0001]    The present invention relates to new pharmaceutical compositions for inhalation based on tiotropium salts and salts of salmeterol which do not dissolve easily, process for preparing them and their use in the treatment of respiratory complaints.  
         BACKGROUND TO THE INVENTION  
         [0002]    The compound tiotropium bromide, a salt of tiotropium, is known from European Patent Application EP 418 716 A1 and has the following chemical structure:  
                         
 
           [0003]    This compound can also be known by the chemical name (1α,2β,4β,5α,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0 2,4 ]nonane-bromide and has valuable pharmacological properties. The term tiotropium should be understood within the scope of the present invention as being a reference to the free cation.  
           [0004]    Like other salts of tiotropium, it is a highly effective anticholinergic and can therefore provide therapeutic benefit in the treatment of asthma or COPD (chronic obstructive pulmonary disease).  
           [0005]    Tiotropium salts are preferably administered by inhalation. Suitable inhalable powders packed into appropriate capsules (inhalettes) may be used, administered by means of corresponding powder inhalers. Alternatively, they may be administered by the use of suitable inhalable aerosols. These also include powdered inhalable aerosols which contain, for example, HFA134a, HFA227 or mixtures thereof as propellant gas. They may also be administered in the form of suitable solutions of the tiotropium salt.  
         DETAILED DESCRIPTION OF THE INVENTION  
         [0006]    Surprisingly, an unexpectedly beneficial therapeutic effect, particularly a synergistic effect can be observed in the treatment of inflammatory or obstructive respiratory complaints if one or more, preferably one, anticholinergic is used with one or more corticosteroids and with one or more tiotropium salts (1) are used in conjunction with one or more salmeterol salts (2).  
           [0007]    This significantly reduces undesirable side effects, for example, which are frequently observed when β-mimetics such as salmeterol are administered to humans. Examples of central side effects of β-mimetics include, for example, general malaise, excitement, sleeplessness, anxiety, trembling fingers, sweating and headaches.  
           [0008]    The term tiotropium is intended within the scope of the present invention as a reference to the free cation (1′). Any reference to salmeterol is intended within the scope of the present invention as a reference to the free base (2′). The preparation of salmeterol was first described in British Patent GB 2140800 to the content of which reference is hereby made.  
           [0009]    The active substance combinations according to the invention are surprisingly also characterised both by a rapid onset of activity and by their long-lasting effect. This is very important to the patient as on the one hand they will rapidly experience an improvement in their condition after taking the combination and on the other hand because of the long-lasting effect it is sufficient to take the drug once a day.  
           [0010]    The abovementioned effects are observed both when the two active substances are taken simultaneously in a single active substance formulation and when they are administered successively in separate formulations. It is preferable according to the invention to administer the two active substance ingredients simultaneously in a single formulation.  
           [0011]    In one aspect the present invention relates to a pharmaceutical composition which contains one or more tiotropium salts 1 and one or more salmeterol salts 2, optionally in the form of their solvates or hydrates. The active substances may either be combined in a single preparation or contained in two separate formulations. Pharmaceutical compositions which contain the active substances 1 and 2 in a single preparation are preferred according to the invention.  
           [0012]    In another aspect the present invention relates to a pharmaceutical composition which contains, in addition to therapeutically effective quantities of 1 and 2, a pharmaceutically acceptable excipient. In one aspect the present invention relates to a pharmaceutical composition which does not contain any pharmaceutically acceptable excipient in addition to therapeutically effective quantities of 1 and 2.  
           [0013]    The present invention also relates to the use of 1 and 2 for preparing a pharmaceutical composition containing therapeutically effective quantities of 1 and 2 for treating inflammatory or obstructive diseases of the respiratory tract, particularly asthma and/or COPD, by simultaneous or successive administration.  
           [0014]    The present invention also relates to the simultaneous or successive use of therapeutically effective doses of the combination of the above pharmaceutical compositions 1 and 2 for treating inflammatory or obstructive diseases of the respiratory tract, particularly asthma or COPD.  
           [0015]    By the tiotropium salts 1 which may be used within the scope of the present invention are meant the compounds which contain, in addition to tiotropium as counter-ion (anion), chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methyl sulphate. Within the scope of the present invention, the methanesulphonate, chloride, bromide and iodide are preferred of all the tiotropium salts 1, the methanesulphonate and bromide being of particular importance. Of outstanding importance according to the invention is tiotropium bromide.  
           [0016]    By salts of salmeterol 2 are meant, according to the invention, pharmaceutically acceptable salts of salmeterol, particularly salts of salmeterol of limited solubility. Preferred salts are those which have a solubility in water of 0.1 mg/ml or less, preferably 0.01 mg/ml (buffer pH 6.8).  
           [0017]    Preferably, the organic acids listed below are used as salt-forming agents.  
                         

                         
 
           [0018]    According to the invention, salmeterol salts 2 selected from the following are preferred:  
           [0019]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-biphenyl-4-carboxylate  
           [0020]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-chlorosalicylate  
           [0021]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,4-dihydroxybenzoate  
           [0022]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2-hydroxy-3-naphthoic acid  
           [0023]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-1-hydroxy-2-naphthoate  
           [0024]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-salicylate  
           [0025]    The following salmeterol salts of formula 2 may be prepared analogously to the methods described hereinbefore:  
                         
 
           [0026]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-hydroxy-1-naphthoate  
           [0027]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,5-dichloro-salicylate  
           [0028]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-furan-2-carboxylate  
           [0029]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,5-dihydroxy-terephthoate  
           [0030]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-cinnamoylate  
           [0031]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-triphenyl-acetate  
           [0032]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-phenyl-cinnamoylate  
           [0033]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-biphenyl-2-carboxylate  
           [0034]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-trans-4-trifluoromethyl-cinnamoylate  
           [0035]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-9-fluorenylideneacetic acid  
           [0036]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-(2-naphthyl)acrylate  
           [0037]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-(1-naphthyl)acrylate  
           [0038]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-1-naphthoate  
           [0039]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,6-dichlorobenzoate  
           [0040]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,4-dichlorobenzoate  
           [0041]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,5-dichlorobenzoate  
           [0042]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-bromobenzoate  
           [0043]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-trifluoromethylbenzoate  
           [0044]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-isopropyl-benzoate  
           [0045]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-tert.butylbenzoate  
           [0046]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-(3-indolyl)-acrylate  
           [0047]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,4-dichloro-cinnamoylate  
           [0048]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,6-dichloro-cinnamoylate  
           [0049]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,5-dimethoxy-cinnamoylate  
           [0050]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2-trifluoromethyl-cinnamoylate  
           [0051]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-trifluoromethyl-cinnamoylate  
           [0052]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-chloro-cinnamoylate  
           [0053]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,4-dichloro-cinnamoylate  
           [0054]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-bromo-cinnamoylate  
           [0055]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-chloro-cinnamoylate  
           [0056]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-methoxy-cinnamoylate  
           [0057]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-fluoro-cinnamoylate  
           [0058]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-isopropyl-cinnamoylate  
           [0059]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-tert-butyl-cinnamoylate  
           [0060]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,6-difluoro-cinnamoylate  
           [0061]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,4-difluoro-cinnamoylate  
           [0062]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,4-difluoro-cinnamoylate  
           [0063]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4,5-trifluoro-cinnamoylate  
           [0064]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,4,5-trifluoro-cinnamoylate  
           [0065]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-methoxy-salicylate  
           [0066]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-methoxy-salicylate  
           [0067]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-methoxy-saliate  
           [0068]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-methylsalicylic acid  
           [0069]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-amino-salicylate  
           [0070]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-chloro-salicylate  
           [0071]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-sulfo-salicylate  
           [0072]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-acetyl-salicylate  
           [0073]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,5-diiodo-salicylic acid  
           [0074]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-isoquinoline-1-carbonoxylate  
           [0075]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-9-fluorenecarboxylate  
           [0076]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-9-fluorenon-1-carboxylate  
           [0077]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,5-diisopropyl-salicylate  
           [0078]    4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-diflunisal  
                                                       Melting point                   (from DSC)       Salt-forming agent           Salmeterol salt       (Acid)   Name   Crystallised from   T fus  [° C.]                                                                     2-Hydroxy-1- naphthoic acid   Ethyl acetate   122                                             3,5-Dichloro- salicylic acid   Diethylether   108                                             Furan- 2-carboxylic acid   Diethylether    80                                             2,5-Dihydroxy- terephthalic acid   Ethyl acetate   102                                             cinnamic acid   Ethyl acetate    89                                             Triphenyl- acetic acid   Diethylether   116                                             4-Phenyl- cinnamic acid   Ethyl acetate   109                                             Biphenyl-2- carboxylic acid   Ethyl acetate   127                                             Trans-4- Trifluoromethyl- cinnamic acid   Ethyl acetate   125                                             9- Fluorenylideneacetic acid   Ethyl acetate    88                                             3-(2- Naphthyl)acrylic acid   Ethyl acetate    97                                             3-(1- Naphthyl)acrylic acid   Ethyl acetate    77                                             1-Naphthoic acid   Ethyl acetate   120                                             2,6 Dichlorobenzoic acid   Ethyl acetate   103                                             3,4 Dichlorobenzoic acid   Ethyl acetate   115                                             3,5 Dichlorobenzoic acid   Ethyl acetate   110                                             4- Bromobenzoic acid   Ethyl acetate   115                                             4- Trifluoromethyl- benzoic acid   Ethyl acetate   125                                             4-Isopropyl- benzoic acid   Ethyl acetate   85/90 (two phase mixture)                                             4-tert.- Butylbenzoic acid   Ethyl acetate    95                                             3-(3-Indolyl)- acrylic acid   Ethyl acetate   113                                             2,4- dichlorocinnamic acid   Ethyl acetate   138                                             2,6- dichlorocinnamic acid   Ethyl acetate    82                                             2,5-Dimethoxy- cinnamic acid   Ethyl acetate    88                                             2-Trifluoromethyl cinnamic acid   Ethyl acetate    94                                             3-Trifluoromethyl cinnamic acid   Ethyl acetate    92                                             3-Chlorocinnamic acid   Ethyl acetate    90                                             3,4- dichlorocinnamic acid   Ethyl acetate   116                                             4-bromocinnamic acid   Ethyl acetate   127                                             4-Chlorocinnamic acid   Ethyl acetate   123                                             4-Methoxycinnamic acid   Ethyl acetate    98                                             4-Fluorocinnamic acid   Ethyl acetate   113                                             4-Isopropyl cinnamic acid   Ethyl acetate    82                                             4-tert- Butylcinnamic acid   Ethyl acetate    93                                             2,6- Difluorocinnamic acid   Ethyl acetate    77                                             2,4- Difluorocinnamic acid   Ethyl acetate   121                                             3,4- Difluorocinnamic acid   Ethyl acetate   102                                             2,4,5- Trifluorocinnamic acid   Ethyl acetate   120                                             3,4,5- Trifluorzimtsäure   Ethyl acetate   107                                             3-Methoxy- salicylic acid   Ethyl acetate   118                                             4-Methoxy- salicylic acid   Ethyl acetate   113                                             5-Methoxy- salicylic acid   Ethyl acetate   114                                             4-Methyl- salicylic acid   Ethyl acetate   116                                             5-Amino- salicylic acid   Ethyl acetate/ iso-Propanol   146                                             3-Chloro-salicylic acid   Ethyl acetate   108                                             5-Sulfo-salicylic acid   Ethyl acetate/ iso-Propanol   129                                             5-Acetyl- salicylic acid   Ethyl acetate    80                                             3,5-diiodo- salicylic acid   Ethyl acetate   133                                             Isoquinolin-1- carboxylic acid   Ethyl acetate   105                                             9- Fluorenecarboxylic acid   Ethyl acetate    90                                             9-Fluorenone-1- carboxylic acid   Ethyl acetate/ iso-Propanol   136                                             3,5-Diisopropyl- salicylic acid   Ethyl acetate   115                                             ″Diflunisal″   Ethyl acetate   104                  
 
           [0079]    In the active substance combinations of 1 and 2 according to the invention, ingredients 1 and 2 may be present in the form of their enantiomers, mixtures of enantiomers or in the form of racemates.  
           [0080]    The proportions in which the active substances 1 and 2 may be used in the active substance combinations according to the invention are variable. Active substances 1 and 2 may possibly be present in the form of their solvates or hydrates. Depending on the choice of the compounds 1 and 2, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various salt forms The weight ratios given below were therefore based on the tiotropium cation 1′ and the free base of salmeterol 2′. The active substance combinations according to the invention may contain 1 and 2 in ratios by weight ranging from 1:300 to 30:1, preferably from 1:230 to 20:1, more preferably from 1:150 to 10:1, more preferably from 1:50 to 5:1, most preferably from 1:35 to 2:1. Of particular interest according to the invention are pharmaceutical compositions containing the combination of 1′ and 2′ in a weight ratio in the range from 1:25 to 1:1. preferably in the range from 1:10 to 1:2, most preferably in the range from 1:5 to 1:2.5.  
           [0081]    For example and without restricting the scope of the invention thereto, preferred combinations of 1 and 2 according to the invention may contain tiotropium 1′ and salmeterol 2′ in the following weight ratios: 1:40; 1:20; 1:11.1; 1:10; 1:5.6; 1:5; 1:2.8; 1:2.5; 1:1.4; 1:1.25; 1.44:1, 1.6:1.  
           [0082]    The pharmaceutical compositions according to the invention containing the combinations of 1 and 2 are preferably prepared by administering tiotropium 1′ and salmeterol 2′ together in doses of 0.01 to 10000 μg, preferably from 0.1 to 2000 μg, more preferably from 1 to 1000 μg, preferably also from 5 to 500 μg, preferably according to the invention from 10 to 200 μg, preferably from 20 to 100 μg, most preferably from 30 to 70 μg per single dose.  
           [0083]    For example, combinations of 1 and 2 according to the invention contain an amount of tiotropium 1′ and salmeterol 2′ such that the total dosage per single dose is 30 μg, 35 μg, 45 μg, 55 μg, 60 μg, 65 μg, 90 μg, 105 μg, 110 μg, 110 μg, 140 μg or similar. In these dosage ranges the active substances 1′ and 2′ are present in the weight ratios described hereinbefore.  
           [0084]    For example and without restricting the scope of the invention thereto, the combinations of 1 and 2 according to the invention may contain an amount of tiotropium 1′ and salmeterol 2′ such that in each individual dose 5 μg of 1′ and 25 μg of 2′, 5 μg of 1′ and 50 μg of 2′, 5 μg of 1′ and 100 μg of 2′, 5 μg of 1′ and 200 μg of 2′, 10 μg of 1′ and 25 μg of 2′, 10 μg of 1′ and 50 μg of 2′, 10 μg of 1′ and 100 μg of 2′, 10 μg of 1′ and 200 μg of 2′, 18 μg of 1′ and 25 μg of 2′, 18 μg of 1′ and 50 μg of 2′, 18 μg of 1′ and 100 μg of 2′, 18 μg of 1′ and 200 μg of 2′, 20 μg of 1′ and 25 μg of 2′, 20 μg of 1′ and 50 μg of 2′, 20 μg of 1′ and 100 μg of 2′, 20 μg of 1′ and 200 μg of 2′, 36 μg of 1′ and 25 μg of 2′, 36 μg of 1′ and 50 μg of 2′, 36 μg of 1′ and 100 μg of 2′, 36 μg of 1′ and 200 μg of 2′, 40 μg of 1′ and 25 μg of 2′, 40 μg of 1′ and 50 μg of 2′, 40 μg of 1′ and 100 μg of 2′ or 40 μg of 1′ and 200 μg of 2′ are administered.  
           [0085]    If the active substance combination wherein 1 denotes tiotropium bromide and 2 denotes salmeterol x salt is used as the preferred combination of 1 and 2 according to the invention, the quantities of active substances 1′ and 2′ administered per single dose as mentioned above by way of example correspond to the following quantities of 1 and 2 administered per single dose: 6 μg of 1 and 27.9 μg of 2, 6 μg of 1 and 55.9 μg of 2, 6 μg of 1 and 111.8 μg of 2, 6 μg of 1 and 223.6 μg of 2, 12 μg of 1 and 27.9 μg of 2, 12 μg of 1 and 55.9 μg of 2, 12 μg of 1 and 111.8 μg of 2, 12 μg of 1 and 223.6 μg of 2, 21.7 μg of 1 and 27.9 μg of 2, 21.7 μg of 1 and 55.9 μg of 2, 21.7 μg of 1 and 111.8 μg of 2, 21.7 μg of 1 and 223.6 μg of 2, 24.1 μg of 1 and 27.9 μg of 2, 24.1 μg of 1 and 55.9 μg of 2, 24.1 μg of 1 and 111.8 μg of 2, 24.1 μg of 1 and 223.6 μg of 2, 43.3 μg of 1 and 27.9 μg of 2, 43.3 μg of 1 and 55.9 μg of 2, 43.3 μg of 1 and 111.8 μg of 2, 43.3 μg of 1 and 223.6 μg of 2, 48.1 μg of 1 and 27.9 μg of 2, 48.1 μg of 1 and 55.9 μg of 2, 48.1 μg of 1 and 111.8 μg of 2 or 48.1 μg of 1 and 223.6 μg of 2.  
           [0086]    If in the preferred combination of 1 and 2 according to the invention wherein 2 denotes salmeterol x salt, tiotropium bromide monohydrate is used as component 1, for example, the quantities of active substances 1′ and 2′ administered per single dose as mentioned above by way of example correspond to the following quantities of 1 and 2 administered per single dose: 6.2 μg of 1 and 27.9 μg of 2, 6.2 μg of 1 and 55.9 μg of 2, 6.2 μg of 1 and 111.8 μg of 2, 6.2 μg of 1 and 223.6 μg of 2, 12.5 μg of 1 and 27.9 μg of 2, 12.5 μg of 1 and 55.9 μg of 2, 12.5 μg of 1 and 111.8 μg of 2, 12.5 μg of 1 and 223.6 μg of 2, 22.5 μg of 1 and 27.9 μg of 2, 22.5 μg of 1 and 55.9 μg of 2, 22.5 μg of 1 and 111.8 μg of 2, 22.5 μg of 1 and 223.6 μg of 2, 25 μg of 1 and 27.9 μg of 2, 25 μg of 1 and 55.9 μg of 2, 25 μg of 1 and 111.8 μg of 2, 25 μg of 1 and 223.6 μg of 2, 45 μg of 1 and 27.9 μg of 2, 45 μg of 1 and 55.9 μg of 2, 45 μg of 1 and 111.8 μg of 2, 45 μg of 1 and 223.6 μg of 2, 50 μg of 1 and 27.9 μg of 2, 50 μg of 1 and 55.9 μg of 2, 50 μg of 1 and 111.8 μg of 2 or 50 μg of 1 and 223.6 μg of 2.  
           [0087]    The active substance combinations of 1 and 2 according to the invention are preferably administered by inhalation. For this purpose, ingredients 1 and 2 have to be made available in forms suitable for inhalation. Inhalable preparations include inhalable powders or metering aerosols containing propellant gase. Inhalable powders according to the invention containing the combination of active substances 1 and 2 may consist of the active substances on their own or of a mixture of the active substances with physiologically acceptable excipients. The preparations according to the invention may contain the combination of active substances 1 and 2 either together in one formulation or in two separate formulations. These formulations which may be used within the scope of the present invention are described in more detail in the next part of the specification.  
           [0088]    A) Inhalable Powder Containing the Combinations of Active Substances 1 and 2 According to the Invention:  
           [0089]    The inhalable powders according to the invention may contain 1 and 2 either on their own or in admixture with suitable physiologically acceptable excipients.  
           [0090]    If the active substances 1 and 2 are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients. 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, while lactose monohydrate is most particularly preferred.  
           [0091]    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. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of 1 to 9 μm to the excipient mentioned above. These finer excipients are also selected from the group of possible excipients listed hereinbefore. Finally, in order to prepare the inhalable powders according to the invention, micronised active substance 1 and 2 preferably with an average particle size of 0.5 to 10 μm, more preferably from 1 to 5 μm, is added to the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronising and by finally mixing the ingredients together are known from the prior art. The inhalable powders according to the invention may be prepared and administered either in the form of a single powder mixture which contains both 1 and 2 or in the form of separate inhalable powders which contain only 1 and 2.  
           [0092]    The inhalable powders according to the invention may be administered using inhalers known from the prior art. Inhalable powders according to the invention which contain a physiologically acceptable excipient in addition to 1 and 2 may be administered, for example, by means of inhalers which deliver a single dose from a supply using a measuring chamber as described in U.S. Pat. No. 4,570,630A, or by other means as described in DE 36 25 685 A. Preferably, the inhalable powders according to the invention which contain physiologically acceptable excipients in addition to 1 and 2 are packed into capsules (to produce so-called inhalettes) which are used in inhalers as described, for example, in WO 94/28958.  
           [0093]    If the inhalable powders according to the invention are to be packed into capsules (inhalettes) for the preferred use described above, the quantities packed into each capsule should be 1 to 30 mg, preferably 3 to 20 mg, more particularly 5 to 10 mg of inhalable powder per capsule. These capsules contain, according to the invention, either together or separately, the doses of 1′ and 2′ mentioned hereinbefore for each single dose.  
           [0094]    B) Propellant Gas-Driven Inhalation Aerosols Containing the Combinations of Active Substances 1 and 2:  
           [0095]    Inhalation aerosols containing propellant gas according to the invention may contain substances 1 and 2 dissolved in the propellant gas or in dispersed form. 1 and 2 may be present in separate formulations or in a single preparation, in which 1 and 2 are either each dissolved, dispersed or only one component is dissolved and the other is dispersed. The propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as chlorinated or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above may be used on their own or in mixtures thereof. Particularly preferred propellant gases are halogenated alkane derivatives selected from among TG11, TG12, TG134a and TG227. Of the halogenated hydrocarbons mentioned above, TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof are preferred.  
           [0096]    The propellant-driven inhalation aerosols according to the invention may also contain other ingredients such as co-solvents, stabilisers, surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the art.  
           [0097]    The inhalation aerosols containing propellant gas according to the invention may contain up to 5 wt.-% of active substance 1 and/or 2. Aerosols according to the invention contain, for example, 0.002 to 5 wt.-%, 0.01 to 3 wt.-%, 0.015 to 2 wt.-%, 0.1 to 2 wt.-%, 0.5 to 2 wt.-% or 0.5 to 1 wt.-% of active substance 1 and/or 2.  
           [0098]    If the active substances 1 and/or 2 are present in dispersed form, the particles of active substance preferably have an average particle size of up to 10 μm, preferably from 0.1 to 5 μm, more preferably from 1 to 5 μm.  
           [0099]    The propellant-driven inhalation aerosols according to the invention mentioned above may be administered using inhalers known in the art (MDIs=metered dose inhalers). Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of propellant-driven aerosols as hereinbefore described combined with one or more inhalers suitable for administering these aerosols. In addition, the present invention relates to inhalers which are characterised in that they contain the propellant gas-containing aerosols described above according to the invention. The present invention also relates to cartridges which are fitted with a suitable valve and can be used in a suitable inhaler and which contain one of the above-mentioned propellant gas-containing inhalation aerosols according to the invention. Suitable cartridges and methods of filling these cartridges with the inhalable aerosols containing propellant gas according to the invention are known from the prior art.  
           [0100]    The following Examples serve to illustrate the present invention further without restricting the scope of the invention to the following embodiments provided by way of example.  
           [0101]    Starting Materials  
           [0102]    Tiotropium Bromide:  
           [0103]    The tiotropium bromide used in the following formulation examples may be obtained as described in European Patent Application 418 716 A1.  
           [0104]    In order to prepare the inhalable powders according to the invention, crystalline tiotropium bromide monohydrate may also be used. This crystalline tiotropium bromide monohydrate may be obtained by the method described below.  
           [0105]    15.0 kg of tiotropium bromide are placed in 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80-90° C. and stirred at constant temperature until a clear solution is formed. Activated charcoal (0.8 kg) moistened with water is suspended in 4.4 kg of water, this mixture is added to the solution containing the tiotropium bromide and the resulting mixture is rinsed with 4.3 kg of water. The mixture thus obtained is stirred for at least 15 minutes at 80-90° C. and then filtered through a heated filter into an apparatus preheated to an external temperature of 70° C. The filter is rinsed with 8.6 kg of water. The contents of the apparatus are cooled at 3-5° C. for every 20 minutes to a temperature of 20-25° C. The apparatus is cooled further to 10-15° C. using cold water and crystallisation is completed by stirring for at least another hour. The crystals are isolated using a suction filter dryer, the crystal slurry isolated is washed with 9 litres of cold water (10-15° C.) and cold acetone (10-15° C.). The crystals obtained are dried at 25° C. in a nitrogen current over a period of 2 hours.  
           [0106]    Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory).  
           [0107]    The crystalline tiotropium bromide monohydrate thus obtained is micronised by known methods in order to prepare the active substance in the form of the average particle size corresponding to the specifications according to the invention.  
           [0108]    Salmeterol x Salt  
           [0109]    Where the examples that follow refer to salmeterol x salt, this was obtained as follows: 
       
    
    
     EXAMPLE 1  
     4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-biphenyl-4-carboxylate  
       [0110]    2.5 g (6 mmol) of salmeterol base are dissolved in 25 mL of ethyl acetate while heating. To this solution is added a solution, prepared by heating, of 1.19 g (6 mmol) of biphenyl-4-carboxylic acid in 25 mL of ethyl acetate. A clear solution is obtained from which the salt crystallises out. The colourless suspension is stirred for 16 hours at ambient temperature and then for 1 to 2 hours at 0° C. The solid is filtered off, washed with cold ethyl acetate and tert. butylmethylether and dried in a vacuum drying cupboard at 40 to 45° C. 3.2 g (87% of theory) of the title salt are obtained as a colourless solid.  
         [0111]    Melting point 79.5-80° C.  
         [0112]    The following salts (Examples 2 to 6) are prepared analogously from the salmeterol base.  
       EXAMPLE 2  
     4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-chlorosalicylate (Salt)  
       [0113]    Melting point: 122.5-123° C.  
       EXAMPLE 3  
     4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,4-dihydroxybenzoate (Salt) as a Resin-Like Solid  
     EXAMPLE 4  
     4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2-hydroxy-3-naphthoic Acid (Salt)  
       [0114]    Melting point: 114.5-115° C.  
       EXAMPLE 5  
     4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-1-hydroxy-2-naphthoic Acid (Salt)  
       [0115]    Melting point: 136.5-137° C.  
       EXAMPLE 6  
     4-Hydroxy-α 1 -[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-salicylate (Salt) as a Resin-Like Solid  
     FORMULATION EXAMPLES  
       [0116]    A) Powder for Inhalation:  
                                                                           Ingredients   μg per capsule                                        1)                tiotropium bromide monohydrate   10.8           salmeterol × salt   27.9           lactose   4961.3           Total   5000           2)           tiotropium bromide monohydrate   21.7           salmeterol × salt   55.9           lactose   4922.4           Total   5000           3)           tiotropium bromide × H 2 O   22.5           salmeterol × salt   55.9           lactose   4921.6           Total   5000                      
 
         [0117]    B) Inhalable Aerosols Containing Propellant Gas:  
                                                                 Ingredients   Wt %                                        1) Suspension aerosol:               tiotropium bromide   0.015           salmeterol × salt   0.066           soya lecithin   0.2           TG 11:TG 12 = 2:3   ad 100           2) Suspension aerosol:           tiotropium bromide   0.029           salmeterol × salt   0.033           absolute ethanol   0.5           isopropyl myristate   0.1           TG 227   ad 100           tiotropium bromide   0.029           salmeterol × salt   0.033           TG 227 or TG 134a   ad 100