Synergistic combination

Abstract

The invention relates to the combined administration of PDE inhibitors and β2 adrenoceptor agonists for the treatment of respiratory disorders.

1 - 12 . (canceled)  
   
   
       13 . A pharmaceutical composition comprising a PDE inhibitor, which is to be administered orally, from the PDE4 or PDE3/4 inhibitors group combined with a β 2  adrenoceptor agonist in fixed or free combination, wherein said PDE inhibitor is selected from the group consisting of roflumilast; AWD-12-281; SB-207499; arofylline; ibudilast; a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof; and an N-oxide of roflumilast, 
 and wherein said β 2  adrenoceptor agonist is selected from the group consisting of 4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol (salbutamol); (R)-4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol (levosalbutamol); 1-(3,5-dihydroxyphenyl)-2-(tert-butylamino)-ethanol (terbutaline); 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-tert-butylaminoethyl)pyridine (pirbuterol); (R*,R*)-(±)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide (formoterol); (±)-4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol (salmeterol); and a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.    
   
   
       14 . The pharmaceutical composition as claimed in  claim 13 , which is a fixed oral combination.  
   
   
       15 . The pharmaceutical composition as claimed in  claim 13 , wherein the PDE inhibitor is a compound selected from the group consisting of arofylline; ibudilast; SB-207499; and a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.  
   
   
       16 . The pharmaceutical composition as claimed in  claim 13 , wherein the PDE inhibitor is roflumilast or a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof, or an N-oxide of roflumilast.  
   
   
       17 . The pharmaceutical composition as claimed in  claim 13 , wherein the PDE inhibitor is roflumilast or a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof, or an N-oxide of roflumilast, and the β 2  adrenoceptor agonist is (±)-4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol (salmeterol) or a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.  
   
   
       18 . The pharmaceutical composition as claimed in  claim 13 , wherein the β 2  adrenoceptor agonist is selected from the group consisting of 4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol (salbutamol); 1-(3,5-dihydroxyphenyl)-2-(tert-butylamino) ethanol (terbutaline); and a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.  
   
   
       19 . The pharmaceutical composition as claimed in  claim 13 , wherein the PDE inhibitor is selected from the group consisting of arofylline; ibudilast; SB-207499; and a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof, 
 and the β 2  adrenoceptor agonist is selected from the group consisting of 4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol (salbutamol); 1-(3,5-dihydroxyphenyl)-2-(tert-butylamino)ethanol (terbutaline); and a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.    
   
   
       20 . The pharmaceutical composition as claimed in  claim 13 , wherein the PDE inhibitor is roflumilast or a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof, or an N-oxide of roflumilast, and the β 2  adrenoceptor agonist is selected from the group consisting of 4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol (salbutamol); 1-(3,5-dihydroxyphenyl)-2-(tert-butylamino)ethanol (terbutaline); and a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.  
   
   
       21 . A method of treating a respiratory tract disorder in a patient, comprising administering a therapeutically effective amount of a PDE inhibitor from the PDE4- or PDE3/4 inhibitors group in combination with a β 2  adrenoceptor agonist to said patient, wherein said PDE inhibitor is administered orally, wherein said PDE inhibitor is selected from the group consisting of roflumilast; AWD-12-281; SB-207499; arofylline; ibudilast; a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt, or solvate of a salt thereof; and an N-oxide of roflumilast, 
 and wherein said β 2  adrenoceptor agonist is selected from the group consisting of 4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol (salbutamol); (R)-4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol (levosalbutamol); 1-(3,5-dihydroxyphenyl)-2-(tert-butylamino)-ethanol (terbutaline); 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-tert-butylaminoethyl)pyridine (pirbuterol); (R*,R*)-(±)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide (formoterol); (±)-4-hydroxy-α 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol (salmeterol); and a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.    
   
   
       22 . The pharmaceutical composition as claimed in  claim 13 , wherein the PDE inhibitor is roflumilast or a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof, or an N-oxide of roflumilast, and the β 2  adrenoceptor agonist is (R*,R*)-(±)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide (formoterol) or a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.  
   
   
       23 . The pharmaceutical composition as claimed in  claim 13 , which additionally contains an excipient selected from the group consisting of propellants, surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers, solvents, gel-forming agents, tablet excipients, antioxidants, dispersants, antifoams, flavor corrigents, solubilizers, colorants or permeation promoters, and complexing agents.  
   
   
       24 . The method of  claim 21 , wherein the respiratory tract disorder is an allergen-induced or inflammation-induced bronchial disorder.  
   
   
       25 . The method of  claim 24 , wherein the allergen-induced or inflammation-induced bronchial disorder is selected from the group consisting of bronchitis, obstructive bronchitis, spastic bronchitis, allergic bronchitis, allergic asthma, bronchial asthma, and COPD.  
   
   
       26 . The method of  claim 21 , wherein the PDE inhibitor and the β 2  adrenoceptor agonist are administered simultaneously.  
   
   
       27 . The method of  claim 21 , wherein the PDE inhibitor and the β 2  adrenoceptor agonist are administered more or less simultaneously.  
   
   
       28 . The method of  claim 21 , wherein the PDE inhibitor and the β 2  adrenoceptor agonist are administered in succession.  
   
   
       29 . A method of treating a respiratory tract disorder in a patient, comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition as claimed in  claim 17 .  
   
   
       30 . The method of  claim 29 , wherein the respiratory tract disorder is an allergen-induced or inflammation-induced bronchial disorder.  
   
   
       31 . The method of  claim 30 , wherein the allergen-induced or inflammation-induced bronchial disorder is selected from the group consisting of bronchitis, obstructive bronchitis, spastic bronchitis, allergic bronchitis, allergic asthma, bronchial asthma, and COPD.  
   
   
       32 . The method of  claim 29 , wherein the PDE inhibitor and the β 2  adrenoceptor agonist are administered simultaneously.  
   
   
       33 . The method of  claim 29 , wherein the PDE inhibitor and the β 2  adrenoceptor agonist are administered more or less simultaneously.  
   
   
       34 . The method of  claim 29 , wherein the PDE inhibitor and the β 2  adrenoceptor agonist are administered in succession.  
   
   
       35 . A method of treating a respiratory tract disorder in a patient, comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition as claimed in  claim 20 .  
   
   
       36 . The method of  claim 35 , wherein the respiratory tract disorder is an allergen-induced or inflammation-induced bronchial disorder.  
   
   
       37 . The method of  claim 36 , wherein the allergen-induced or inflammation-induced bronchial disorder is selected from the group consisting of bronchitis, obstructive bronchitis, spastic bronchitis, allergic bronchitis, allergic asthma, bronchial asthma, and COPD.  
   
   
       38 . The method of  claim 35 , wherein the PDE inhibitor and the β 2  adrenoceptor agonist are administered simultaneously.  
   
   
       39 . The method of  claim 35 , wherein the PDE inhibitor and the β 2  adrenoceptor agonist are administered more or less simultaneously.  
   
   
       40 . The method of  claim 35 , wherein the PDE inhibitor and the β 2  adrenoceptor agonist are administered in succession.  
   
   
       41 . A method of treating a respiratory tract disorder in a patient, comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition as claimed in  claim 22 .  
   
   
       42 . The method of  claim 41 , wherein the respiratory tract disorder is an allergen-induced or inflammation-induced bronchial disorder.  
   
   
       43 . The method of  claim 42 , wherein the allergen-induced or inflammation-induced bronchial disorder is selected from the group consisting of bronchitis, obstructive bronchitis, spastic bronchitis, allergic bronchitis, allergic asthma, bronchial asthma, and COPD.  
   
   
       44 . The method of  claim 41 , wherein the PDE inhibitor and the β 2  adrenoceptor agonist are administered simultaneously.  
   
   
       45 . The method of  claim 41 , wherein the PDE inhibitor and the β 2  adrenoceptor agonist are administered more or less simultaneously.  
   
   
       46 . The method of  claim 41 , wherein the PDE inhibitor and the β 2  adrenoceptor agonist are administered in succession.