Pharmaceutical compositions containing tiotropium salts and low-solubility salmeterol salts

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).

1 . A pharmaceutical composition comprising: 
 (a) a tiotropium salt; and    (b) a salmeterol salt having a solubility in water of 0.1 mg/mL or less.    
   
   
       2 . The pharmaceutical composition according to  claim 1 , wherein the tiotropium salt is selected from the group consisting of: tiotropium chloride, tiotropium bromide, tiotropium iodide, tiotropium methanesulfonate, tiotropium p-toluenesulfonate, and tiotropium methylsulfate.  
   
   
       3 . The pharmaceutical composition according to  claim 1 , wherein the tiotropium salt is tiotropium bromide.  
   
   
       4 . A pharmaceutical kit comprising: 
 (a) a pharmaceutical composition comprising a tiotropium salt; and    (b) a pharmaceutical composition comprising a salmeterol salt having a solubility in water of 0.1 mg/mL or less.    
   
   
       5 . The pharmaceutical kit according to  claim 4 , wherein the tiotropium salt is selected from the group consisting of: tiotropium chloride, tiotropium bromide, tiotropium iodide, tiotropium methanesulfonate, tiotropium p-toluenesulfonate, and tiotropium methylsulfate.  
   
   
       6 . The pharmaceutical kit according to  claim 4 , wherein the tiotropium salt is tiotropium bromide.  
   
   
       7 . The pharmaceutical composition according to one of  claims 1  to  3 , wherein the salmeterol salt is an acid addition salt of salmeterol formed with an acid selected from the group consisting of: 2-hydroxy-1-naphthoic acid, 3,5-dichlorosalicylic acid, furan-2-carboxylic acid, 2,5-dihydroxyterephthalic acid, cinnamic acid, triphenylacetic acid, 4-phenylcinnamic acid, biphenyl-2-carboxylic acid, 4-trifluoromethylcinnamic acid, 9-fluorenylideneacetic acid, 3-(2-naphthyl)acrylic acid, 3-(1-naphthyl)acrylic acid, 1-naphthoic acid, 2,6-dichlorobenzoic acid, 3,4-dichlorobenzoic acid, 3,5-dichlorobenzoic acid, 4-bromobenzoic acid, 4-trifluoromethylbenzoic acid, 4-isopropylbenzoic acid, 4-tert-butylbenzoic acid, 3-(3-indolyl)acrylic acid, 2,4-dichlorocinnamic acid, 2,6-dichlorocinnamic acid, 2,5-dimethoxycinnamic acid, 2-trifluoromethylcinnamic acid, 3-trifluoromethylcinnamic acid, 3-chlorocinnamic acid, 3,4-dichlorocinnamic acid, 4-bromocinnamic acid, 4-chlorocinnamic acid, 4-methoxycinnamic acid, 4-fluorocinnamic acid, 4-isopropylcinnamic acid, 4-tert-butylcinnamic acid, 2,6-difluorocinnamic acid, 2,4-difluorocinnamic acid, 3,4-difluorocinnamic acid, 2,4,5-trifluorocinnamic acid, 3,4,5-trifluorocinnamic acid, 3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylic acid, 4-methylsalicylic acid, 5-aminosalicylic acid, 3-chlorosalicylic acid, 5-sulfosalicylic acid, 5-acetylsalicylic acid, 3,5-diiodosalicylic acid, isoquinoline-1-carboxylic acid, 9-fluorenecarboxylic acid, 9-fluorenone-1-carboxylic acid, 3,5-diisopropylsalicylic acid, and diflunisal.  
   
   
       8 . The pharmaceutical composition according to one of  claims 1  to  3 , wherein the salmeterol salt is selected from the group consisting of: 
 4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-phenylcinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-trifluoromethylcinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3,4-dichlorocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-2,4-dichlorocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanolcinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3-(2-naphthyl)acrylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3-(1-naphthyl)acrylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-2,6-dichlorocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-2,5-dimethoxycinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-2-trifluoromethylcinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3-trifluoromethylcinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3-chlorocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-bromocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-chlorocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-methoxycinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-fluorocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-isopropylcinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-tert-butylcinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-2,4-difluorocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3,4-difluorocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-2,4,5-trifluorocinnamate; and    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3,4,5-trifluorocinnamate.    
   
   
       9 . The pharmaceutical composition according to one of  claims 1  to  3 , wherein the salmeterol salt is selected from the group consisting of: 
 4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-5-(2,4-difluorophenyl)salicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3,5-diisopropylsalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-chlorosalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3,5-dichlorosalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-2,5-dihydroxyterephthalate (base:acid=1:2);    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3-methoxysalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-methoxysalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-5-methoxysalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-methylsalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-5-aminosalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3-chlorosalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-5-sulfosalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-5-acetylsalicylate; and    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3,5-diiodosalicylate.    
   
   
       10 . The pharmaceutical kit according to one of  claims 4  to  6 , wherein the salmeterol salt is an acid addition salt of salmeterol formed with an acid selected from the group consisting of: 2-hydroxy-1-naphthoic acid, 3,5-dichlorosalicylic acid, furan-2-carboxylic acid, 2,5-dihydroxyterephthalic acid, cinnamic acid, triphenylacetic acid, 4-phenylcinnamic acid, biphenyl-2-carboxylic acid, 4-trifluoromethylcinnamic acid, 9-fluorenylideneacetic acid, 3-(2-naphthyl)acrylic acid, 3-(1-naphthyl)acrylic acid, 1-naphthoic acid, 2,6-dichlorobenzoic acid, 3,4-dichlorobenzoic acid, 3,5-dichlorobenzoic acid, 4-bromobenzoic acid, 4-trifluoromethylbenzoic acid, 4-isopropylbenzoic acid, 4-tert-butylbenzoic acid, 3-(3-indolyl)acrylic acid, 2,4-dichlorocinnamic acid, 2,6-dichlorocinnamic acid, 2,5-dimethoxycinnamic acid, 2-trifluoromethylcinnamic acid, 3-trifluoromethylcinnamic acid, 3-chlorocinnamic acid, 3,4-dichlorocinnamic acid, 4-bromocinnamic acid, 4-chlorocinnamic acid, 4-methoxycinnamic acid, 4-fluorocinnamic acid, 4-isopropylcinnamic acid, 4-tert-butylcinnamic acid, 2,6-difluorocinnamic acid, 2,4-difluorocinnamic acid, 3,4-difluorocinnamic acid, 2,4,5-trifluorocinnamic acid, 3,4,5-trifluorocinnamic acid, 3-methoxysalicylic acid, 4-methoxysalicylic acid, 5-methoxysalicylic acid, 4-methylsalicylic acid, 5-aminosalicylic acid, 3-chlorosalicylic acid, 5-sulfosalicylic acid, 5-acetylsalicylic acid, 3,5-diiodosalicylic acid, isoquinoline-1-carboxylic acid, 9-fluorenecarboxylic acid, 9-fluorenone-1-carboxylic acid, 3,5-diisopropylsalicylic acid, and diflunisal.  
   
   
       11 . The pharmaceutical kit according to one of  claims 4  to  6 , wherein the salmeterol salt is selected from the group consisting of: 
 4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-phenylcinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-trifluoromethylcinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3,4-dichlorocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-2,4-dichlorocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanolcinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3-(2-naphthyl)acrylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3-(1-naphthyl)acrylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-2,6-dichlorocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-2,5-dimethoxycinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-2-trifluoromethylcinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3-trifluoromethylcinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3-chlorocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-bromocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-chlorocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-methoxycinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-fluorocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-isopropylcinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-tert-butylcinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-2,4-difluorocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3,4-difluorocinnamate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-2,4,5-trifluorocinnamate; and    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3,4,5-trifluorocinnamate.    
   
   
       12 . The pharmaceutical kit according to one of  claims 4  to  6 , wherein the salmeterol salt is selected from the group consisting of: 
 4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-5-(2,4-difluorophenyl)salicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3,5-diisopropylsalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-chlorosalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3,5-dichlorosalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-2,5-dihydroxyterephthalate (base:acid=1:2);    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3-methoxysalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-methoxysalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-5-methoxysalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-4-methylsalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-5-aminosalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3-chlorosalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-5-sulfosalicylate;    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-5-acetylsalicylate; and    4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol-3,5-diiodosalicylate.    
   
   
       13 . The pharmaceutical composition according to one of  claims 1  to  3  or  7  to  9 , wherein the weight ratio of the tiotropium salt to the salmeterol salt, based on the tiotropium cation to salmeterol free base, is in the range of 1:300 to 30:1.  
   
   
       14 . The pharmaceutical composition according to  claim 13 , wherein the weight ratio of the tiotropium salt to the salmeterol salt, based on the tiotropium cation to salmeterol free base, is in the range of 1:230 to 20:1.  
   
   
       15 . The pharmaceutical composition according to one of  claims 1  to  3  or  7  to  9 , wherein a single application corresponds to a dosage of the tiotropium salt to the salmeterol salt, based on the tiotropium cation to salmeterol free base, is 0.01 μg to 1000 μg.  
   
   
       16 . The pharmaceutical composition according to one of  claims 1  to  3  or  7  to  9 , wherein a single application corresponds to a dosage of the tiotropium salt to the salmeterol salt, based on the tiotropium cation to salmeterol free base, is 0.1 μg to 200 μg.  
   
   
       17 . The pharmaceutical composition according to one of  claims 1  to  3  or  7  to  9 , wherein the pharmaceutical composition is in the form of a powder suitable for inhalation.  
   
   
       18 . The pharmaceutical composition according to  claim 17 , wherein the pharmaceutical composition further comprises a physiologically acceptable excipient selected from the group consisting of: monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, and salts.  
   
   
       19 . The pharmaceutical composition according to  claim 18 , wherein the excipient has a maximum mean particle size of up to 250 μm.  
   
   
       20 . The pharmaceutical composition according to  claim 18 , wherein the excipient has a maximum mean particle size of between 10 μm and 150 μm.  
   
   
       21 . A capsule containing a pharmaceutical composition according to  claim 17 .  
   
   
       22 . A capsule containing a pharmaceutical composition according to  claim 18 .  
   
   
       23 . A capsule containing a pharmaceutical composition according to  claim 19 .  
   
   
       24 . A capsule containing a pharmaceutical composition according to  claim 20 .  
   
   
       25 . A pharmaceutical composition consisting essentially of: 
 (a) a tiotropium salt; and    (b) a salmeterol salt having a solubility in water of 0.1 mg/mL or less,    wherein the pharmaceutical composition is in the form of an inhalable powder.    
   
   
       26 . A method of treating respiratory complaints in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition according to one of  claims 1  to  3  or  7  to  9 .  
   
   
       27 . A method of treating asthma or chronic obstructive pulmonary disease (COPD) in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition according to one of  claims 1  to  3  or  7  to  9 .