Inhalable powder containing tiotropium

Abstract

The invention relates to powdered preparations containing tiotropium for inhalation, processes for preparing them as well as their use in preparing a pharmaceutical composition for the treatment of respiratory complaints, particularly for the treatment of COPD (chronic obstructive pulmonary disease) and asthma.

We claim:  
     
         1 . An inhalable powder comprising 0.04 to 0.8% of tiotropium in admixture with a physiologically acceptable excipient, wherein the excipient consists of a mixture of coarser excipient with an average particle size of 15 to 80 μm and finer excipient with an average particle size of 1 to 9 μm, the proportion of the finer excipient constituting 1 to 20% of the total amount of excipient.  
     
     
         2 . An inhalable powder according to  claim 1 , wherein the tiotropium is present in the form of the chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methyl sulphate thereof.  
     
     
         3 . An inhalable powder comprising between 0.048 and 0.96% of tiotropium bromide in admixture with a physiologically acceptable excipient, wherein the excipient consists of a mixture of coarser excipient with an average particle size of 15 to 80 μm and finer excipient with an average particle size of 1 to 9 μm, the proportion of the finer excipient constituting 1 to 20% of the total amount of excipient.  
     
     
         4 . An inhalable powder comprising between 0.05 and 1% of tiotropium bromide monohydrate in admixture with a physiologically acceptable excipient, wherein the excipient consists of a mixture of coarser excipient with an average particle size of 15 to 80 μm and finer excipient with an average particle size of 1 to 9 μm, the proportion of the finer excipient constituting 1 to 20% of the total amount of excipient.  
     
     
         5 . An inhalable powder according to one of claims  1 ,  2 ,  3  or  4 , wherein the excipient consists of a mixture of coarser excipient with an average particle size of 17 to 50 μm and finer excipient with an average particle size of 2 to 8 μm.  
     
     
         6 . An inhalable powder according to one of claims  1 ,  2 ,  3  or  4 , wherein the proportion of finer excipient in the total amount of excipient is 3 to 15%.  
     
     
         7 . An inhalable powder according to one of claims  1 ,  2 ,  3  or  4 , wherein the tiotropium used has an average particle size of 0.5 to 10 μm.  
     
     
         8 . An inhalable powder according to one of claims  1 ,  2 ,  3  or  4 , wherein one or more monosaccharides, disaccharides, oligo- or polysaccharides, polyalcohols, salts thereof, or mixtures thereof are used as the excipients.  
     
     
         9 . An inhalable powder according to  claim 8 , wherein glucose, arabinose, lactose, saccharose, maltose, dextrane, sorbitol, mannitol, xylitol, sodium chloride, calcium carbonate or mixtures thereof are used as the excipients.  
     
     
         10 . An inhalable powder according to  claim 9 , wherein glucose or lactose or mixtures thereof are used as the excipients.  
     
     
         11 . A process for preparing an inhalable powder according to one of  claims 1  to  4 , comprising: (a) mixing coarser excipient fractions with finer excipient fractions to obtain an excipient mixture, and (b) mixing the excipient mixture thus obtained with the tiotropium.  
     
     
         12 . A method of treating a disease that is responsive to the administration of tiotropium, comprising administering to a host in need thereof an inhalable powder according to one of  claims 1  to  4 .  
     
     
         13 . A method according to  claim 12 , wherein the disease is asthma or COPD.  
     
     
         14 . An inhalette capsule containing an inhalable powder according to one of  claims 1  to  4 .  
     
     
         15 . An inhalette capsule containing from 3 to 10 mg of inhalable powder according to one of  claims 1  to  4 .  
     
     
         16 . An inhalette capsule according to  claim 15 , containing between 1.2 and 80 μg of tiotropium.  
     
     
         17 . An inhalable powder according to  claim 4  comprising 0.1 to 0.8% of tiotropium bromide monohydrate.  
     
     
         18 . An inhalable powder according to  claim 4  comprising 0.2 to 0.5% of tiotropium bromide monohydrate.  
     
     
         19 . An inhalable powder according to one of claims  1 ,  2 ,  3  or  4 , wherein the excipient consists of a mixture of coarser excipient with an average particle size of 20 to 30 μm and finer excipient with an average particle size of 3 to 7 μm.  
     
     
         20 . An inhalable powder according to one of claims  1 ,  2 ,  3  or  4 , wherein the proportion of finer excipient in the total amount of excipient is 5 to 10%.  
     
     
         21 . An inhalable powder according to one of claims  1 ,  2 ,  3  or  4 , wherein the tiotropium used has an average particle size of 1 to 6 μm.  
     
     
         22 . An inhalable powder according to one of claims  1 ,  2 ,  3  or  4 , wherein the tiotropium used has an average particle size of 2 to 5 μm.  
     
     
         23 . An inhalable powder according to  claim 10 , wherein lactose monohydrate is used as the excipient.  
     
     
         24 . An inhalable powder comprising between 0.2 and 0.5% of tiotropium bromide monohydrate in admixture with lactose monohydrate as the physiologically acceptable excipient, wherein the excipient consists of a mixture of coarser excipient with an average particle size of 20 to 30 μm and finer excipient with an average particle size of 3 to 7 μm, the proportion of the finer excipient constituting 5 to 10% of the total amount of excipient.  
     
     
         25 . An inhalette capsule containing from 3 to 10 mg of inhalable powder according to  claim 24 .  
     
     
         26 . An inhalette capsule containing from 4 to 6 mg of inhalable powder according to one of  claims 1  to  4  or  24 .  
     
     
         27 . An inhalette capsule according to  claim 26 , containing between 1.6 and 48 μm of tiotropium.  
     
     
         28 . An inhalette capsule according to  claim 26 , containing between 2 and 60 μm of tiotropium bromide monohydrate.  
     
     
         29 . An inhalette capsule according to  claim 26 , containing between 4 and 48 μg of tiotropium bromide monohydrate.  
     
     
         30 . An inhalette capsule according to  claim 26 , containing between 8 and 30 μg of tiotropium bromide monohydrate.  
     
     
         31 . An inhalable powder comprising 0.04 to 0.8% of tiotropium in admixture with a physiologically acceptable excipient, said inhalable powder prepared by a process comprising: (a) mixing coarser excipient having an average particle size of 15 to 80 μm and finer excipient having an average particle size of 1 to 9 μm, wherein the proportion of the finer excipient constitutes 1 to 20% of the total amount of excipient, to obtain an excipient mixture, and (b) mixing the excipient mixture thus obtained with the tiotropium.  
     
     
         32 . An inhalable powder according to  claim 31 , wherein the tiotropium is present in the form of the chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methyl sulphate thereof.  
     
     
         33 . An inhalable powder comprising between 0.048 and 0.96% of tiotropium bromide in admixture with a physiologically acceptable excipient, said inhalable powder prepared by a process comprising: (a) mixing coarser excipient having an average particle size of 15 to 80 μm and finer excipient having an average particle size of 1 to 9 μm, wherein the proportion of the finer excipient constitutes 1 to 20% of the total amount of excipient, to obtain an excipient mixture, and (b) mixing the excipient mixture thus obtained with the tiotropium bromide.  
     
     
         34 . An inhalable powder comprising between 0.05 and 1% of tiotropium bromide monohydrate in admixture with a physiologically acceptable excipient, said inhalable powder prepared by a process comprising: (a) mixing coarser excipient having an average particle size of 15 to 80 μm and finer excipient having an average particle size of 1 to 9 μm, wherein the proportion of the finer excipient constitutes 1 to 20% of the total amount of excipient, to obtain an excipient mixture, and (b) mixing the excipient mixture thus obtained with the tiotropium bromide monohydrate.  
     
     
         35 . An inhalable powder according to  claim 34  comprising 0.1 to 0.8% of tiotropium. bromide monohydrate.  
     
     
         36 . An inhalable powder according to  claim 34  comprising 0.2 to 0.5% of tiotropium bromide monohydrate.  
     
     
         37 . An inhalable powder according to one of claims  31 ,  32 ,  33  or  34 , wherein the coarser excipient has an average particle size of 17 to 50 μm and the finer excipient has an average particle size of 2 to 8 μm.  
     
     
         38 . An inhalable powder according to one of claims  31 ,  32 ,  33  or  34 , wherein the coarser excipient has an average particle size of 20 to 30 μm and the finer excipient has an average particle size of 3 to 7 μm.  
     
     
         39 . An inhalable powder according to one of claims  31 ,  32 ,  33  or  34 , wherein the proportion of finer excipient in the total amount of excipient is 3 to 15%.  
     
     
         40 . An inhalable powder according to one of claims  31 ,  32 ,  33  or  34 , wherein the proportion of finer excipient in the total amount of excipient is 5 to 10%.  
     
     
         41 . An inhalable powder according to one of claims  31 ,  32 ,  33  or  34 , wherein the tiotropium used has an average particle size of 0.5 to 10 μm.  
     
     
         42 . An inhalable powder according to one of claims  31 ,  32 ,  33  or  34 , wherein the tiotropium used has an average particle size of 1 to 6 μm.  
     
     
         43 . An inhalable powder according to one of claims  31 ,  32 ,  33  or  34 , wherein the tiotropium used has an average particle size of 2 to 5 μm.  
     
     
         44 . An inhalable powder according to one of claims  31 ,  32 ,  33  or  34 , wherein one or more monosaccharides, disaccharides, oligo- or polysaccharides, polyalcohols, salts thereof, or mixtures thereof are used as the excipients.  
     
     
         45 . An inhalable powder according to  claim 44 , wherein glucose, arabinose, lactose, saccharose, maltose, dextrane, sorbitol, mannitol, xylitol, sodium chloride, calcium carbonate or mixtures thereof are used as the excipients.  
     
     
         46 . An inhalable powder according to  claim 45 , wherein glucose or lactose or mixtures thereof are used as the excipients.  
     
     
         47 . An inhalable powder according to  claim 46 , wherein lactose monohydrate is used as the excipient.  
     
     
         48 . An inhalable powder comprising between 0.2 and 0.5% of tiotropium bromide monohydrate in admixture with lactose monohydrate as a physiologically acceptable excipient, said inhalable powder prepared by a process comprising: (a) mixing coarser lactose monohydrate excipient having an average particle size of 20 to 30 μm and finer lactose monohydrate excipient having an average particle size of 3 to 7 μm, wherein the proportion of the finer lactose monohydrate excipient constitutes 5 to 10% of the total amount of excipient, to obtain an excipient mixture, and (b) mixing the excipient mixture thus obtained with the tiotropium bromide monohydrate.  
     
     
         49 . A method of treating a disease that is responsive to the administration of tiotropium, comprising administering to a host in need thereof an inhalable powder according to one of claims  31 ,  32 ,  33 ,  34  or  48 .  
     
     
         50 . A method according to  claim 49 , wherein the disease is asthma or COPD.  
     
     
         51 . An inhalette capsule containing an inhalable powder according to one of claims  31 ,  32 ,  33 ,  34  or  48 .  
     
     
         52 . An inhalette capsule containing from 3 to 10 mg of inhalable powder according to one of claims  31 ,  32 ,  33 ,  34  or  48 .  
     
     
         53 . An inhalette capsule containing from 4 to 6 mg of inhalable powder according to one of claims  31 ,  32 ,  33 ,  34  or  48 .  
     
     
         54 . An inhalette capsule according to  claim 53 , containing between 1.6 and 48 μg of tiotropium.  
     
     
         55 . An inhalette capsule according to  claim 53 , containing between 2 and 60 μg of tiotropium bromide monohydrate.  
     
     
         56 . An inhalette capsule according to  claim 53 , containing between 4 and 48 μg of tiotropium bromide monohydrate.  
     
     
         57 . An inhalette capsule according to  claim 53 , containing between 8 and 30 μg of tiotropium bromide monohydrate.