Methods and compositions using terfenadine metabolites in combination with leukotriene inhibitors

Abstract

Methods and pharmaceutical compositions employing a terfenadine metabolite and a leukotriene inhibitor for the treatment or prevention of inflammation or allergic disorders, such as asthma, or symptoms thereof. Also included are methods and compositions employing a terfenadine metabolite, a leukotriene inhibitor, and a decongestant for the treatment or prevention of inflammation or allergic disorders, such as asthma, or symptoms thereof.

What is claimed is:  
     
         1 . A method of treating or preventing asthma or symptoms thereof in a human which comprises administering to a human a therapeutically effective amount of a terfenadine metabolite, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a leukotriene inhibitor, or a pharmaceutically acceptable salt thereof.  
     
     
         2 . A method of treating or preventing asthma or symptoms thereof in a human which comprises administering to a human a composition, said composition comprising (i) a therapeutically effective amount of a terfenadine metabolite, or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of leukotriene inhibitor, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 5-lipoxygenase inhibitors, 5-lipoxygenase activating protein antagonists, and leukotriene receptor antagonists, and mixtures thereof; and a pharmaceutically acceptable carrier or excipient.  
     
     
         3 . The method of  claim 1  or  2  wherein the administering further comprises a therapeutically effective amount of a decongestant, or a pharmaceutically acceptable salt thereof.  
     
     
         4 . The method of  claim 1  wherein said human has asthma.  
     
     
         5 . A method of treating or preventing dermatitis in a human which comprises administering to a human a therapeutically effective amount of a terfenadine metabolite, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a leukotriene inhibitor, or a pharmaceutically acceptable salt thereof.  
     
     
         6 . A method of treating or preventing dermatitis in a human which comprises administering to a human a therapeutically effective amount of a composition, said composition comprising (i) a terfenadine metabolite, or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of leukotriene inhibitor, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 5-lipoxygenase inhibitors, 5-lipoxygenase activating protein antagonists, and leukotriene receptor antagonists, and mixtures thereof; and a pharmaceutically acceptable carrier or excipient.  
     
     
         7 . The method of  claim 5  or  6  wherein the administering further comprises a therapeutically effective amount of a decongestant, or a pharmaceutically acceptable salt thereof.  
     
     
         8 . A method of treating or preventing allergic rhinitis in a human which comprises administering to a human a therapeutically effective amount of a terfenadine metabolite, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a leukotriene inhibitor, or a pharmaceutically acceptable salt thereof.  
     
     
         9 . A method of treating or preventing allergic rhinitis in a human which comprises administering to a human a therapeutically effective amount of a composition, said composition comprising (i) a terfenadine metabolite, or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of leukotriene inhibitor, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 5-lipoxygenase inhibitors, 5-lipoxygenase activating protein antagonists, and leukotriene receptor antagonists, and mixtures thereof; and a pharmaceutically acceptable carrier or excipient.  
     
     
         10 . The method of  claim 8  or  9  wherein the administering further comprises a therapeutically effective amount of a decongestant, or a pharmaceutically acceptable salt thereof.  
     
     
         11 . A method of treating or preventing inflammation in a human which comprises administering to a human a therapeutically effective amount of terfenadine metabolite, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a leukotriene inhibitor, or a pharmaceutically acceptable salt thereof.  
     
     
         12 . A method of treating or preventing inflammation in a human which comprises administering to a human a composition, said composition comprising (i) a therapeutically effective amount of terfenadine metabolite, or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of leukotriene inhibitor, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 5-lipoxygenase inhibitors, 5-lipoxygenase activating protein antagonists, leukotriene receptor antagonists, and mixtures thereof; and a pharmaceutically acceptable carrier or excipient.  
     
     
         13 . The method of  claim 11  or  12  wherein the administering further comprises a therapeutically effective amount of a decongestant, or a pharmaceutically acceptable salt thereof.  
     
     
         14 . A method for treating or preventing a condition responsive to leukotriene inhibition by administering a therapeutically effective amount of terfenadine metabolite, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a leukotriene inhibitor, or a pharmaceutically acceptable salt thereof.  
     
     
         15 . A method of treating or preventing a condition responsive to leukotriene inhibition in a human which comprises administering to a human a composition, said composition comprising (i) a therapeutically effective amount of terfenadine metabolite, or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of leukotriene inhibitor, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 5-lipoxygenase inhibitors, 5-lipoxygenase activating protein antagonists, leukotriene receptor antagonists, and mixtures thereof; and (iii) a pharmaceutically acceptable carrier or excipient.  
     
     
         16 . The method of  claim 14  or  15  wherein the administering further comprises a therapeutically effective amount of a decongestant, or a pharmaceutically acceptable salt thereof.  
     
     
         17 . The method of  claim 14  wherein the condition responsive to leukotriene inhibition comprises asthma or a symptom thereof.  
     
     
         18 . The method of  claim 14  wherein the condition responsive to leukotriene inhibition comprises an allergic condition.  
     
     
         19 . The method of  claim 14  wherein the condition responsive to leukotriene inhibition comprises inflammation.  
     
     
         20 . The method of  claim 1 ,  2 ,  5 ,  6 ,  8 ,  9 ,  11 ,  12 ,  14 , or  15  wherein the terfenadine metabolite is racemic fexofenadine, or a pharmaceutically acceptable salt thereof.  
     
     
         21 . The method of  claim 1 ,  2 ,  5 ,  6 ,  8 ,  9 ,  11 ,  12 ,  14 , or  15  wherein the terfenadine metabolite is (R)-fexofenadine, or a pharmaceutically acceptable salt thereof, substantially free of (S)-fexofenadine.  
     
     
         22 . The method of  claim 1 ,  2 ,  5 ,  6 ,  8 ,  9 ,  11 ,  12 ,  14 , or  15  wherein the terfenadine metabolite is (S)-fexofenadine, or a pharmaceutically acceptable salt thereof, substantially free of (R)-fexofenadine.  
     
     
         23 . The method of  claim 17 ,  18 , or  19  wherein the mount of terfenadine metabolite administered is from about 0.01 mg to about 500 mg per day.  
     
     
         24 . The method of  claim 23  wherein the amount of terfenadine metabolite administered is from about 20 mg to bout 200 mg per day.  
     
     
         25 . The method of  claim 1 ,  2 ,  5 ,  6 ,  8 ,  9 ,  11 ,  12 ,  14 , or  15  wherein the leukotriene inhibitor is a 5-lipoxygenase inhibitor.  
     
     
         26 . The method of  claim 25  wherein the 5-lipoxygenase inhibitor is selected from the group consisting of zileuton, docebenone, piripost, ICI-D2318, and mixtures thereof.  
     
     
         27 . The method of  claim 1 ,  2 ,  5 ,  6 ,  8 ,  9 ,  11 ,  12 ,  14 , or  15  wherein the leukotriene inhibitor is a 5-lipoxygenase activating protein.  
     
     
         28 . The method of  claim 27  wherein the 5-lipoxygenase activating protein is selected from the group consisting of MK-591, MK-886, and mixtures thereof.  
     
     
         29 . The method of  claim 1 ,  2 ,  5 ,  6 ,  8 ,  9 ,  11 ,  12 ,  14 , or  15  wherein the leukotriene inhibitor is a leukotriene receptor antagonist.  
     
     
         30 . The method of  claim 29  wherein the 5-lipoxygenase activating protein is selected from the group consisting of zafirlukast, montelukast, pranlukast, sodium 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethynyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methyl)cyclopropaneacetate; 1-(((1(R)-(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid, and salts and mixtures thereof.  
     
     
         31 . The method of  claim 1 ,  2 ,  5 ,  6 ,  8 ,  9 ,  11 ,  12 ,  14 , or  15  wherein the compositions are administered as a nasal or oral spray.  
     
     
         32 . The method of  claim 1 ,  2 ,  5 ,  6 ,  8 ,  9 ,  11 ,  12 ,  14 , or  15  wherein at least one of the a terfenadine metabolite and the leukotriene inhibitor is administered as a nasal or oral spray.  
     
     
         33 . The method of  claim 1 ,  2 ,  5 ,  6 ,  8 ,  9 ,  11 ,  12 ,  14 , or  15  wherein at least one of the a terfenadine metabolite and the leukotriene inhibitor is administered in an oral solid dosage form.  
     
     
         34 . A pharmaceutical composition which comprises a therapeutically effective amount of a terfenadine metabolite, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a leukotriene inhibitor, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.  
     
     
         35 . The pharmaceutical composition of  claim 34  which further comprises a therapeutically effective amount of a decongestant, or a pharmaceutically acceptable salt thereof.  
     
     
         36 . A pharmaceutical composition which comprises from about 0.01 to about 500 mg of a terfenadine metabolite, or a pharmaceutically acceptable salt thereof, and from about 20 mg to about 2,500 mg of 5-lipoxygenase inhibitor, or a pharmaceutically acceptable salt thereof.  
     
     
         37 . A pharmaceutical composition which comprises from about 0.01 to about 500 mg of a terfenadine metabolite, or a pharmaceutically acceptable salt thereof, and from about 2 mg to about 200 mg of leukotriene receptor antagonist, or a pharmaceutically acceptable salt thereof.  
     
     
         38 . A pharmaceutical composition which comprises from about 0.01 mg to about 500 mg of terfenadine metabolite, or a pharmaceutically acceptable salt thereof, and from about 20 mg to about 2500 mg of 5-lipoxygenase activating protein antagonist, or a pharmaceutically acceptable salt thereof.  
     
     
         39 . The composition of  claim 34 ,  35 ,  36 ,  37 , or  38  wherein the terfenadine metabolite is racemic fexofenadine, or a pharmaceutically acceptable salt thereof.  
     
     
         40 . The composition of  claim 34 ,  35 ,  36 ,  37 , or  38  wherein the terfenadine metabolite comprises (S)-fexofenadine, or a pharmaceutically acceptable salt thereof, substantially free of (R)-fexofenadine.  
     
     
         41 . The composition of  claim 34 ,  35 ,  36 ,  37 , or  38  wherein the terfenadine metabolite comprises (R)-fexofenadine, or a pharmaceutically acceptable salt thereof, substantially free of (S)-fexofenadine.  
     
     
         42 . The composition of  claim 34 ,  35 ,  36 ,  37 , or  38  administered as a nasal or oral spray.  
     
     
         43 . The composition of  claim 34 ,  35 ,  36 ,  37 , or  38  wherein at least one of the a terfenadine metabolite and the leukotriene inhibitor is administered as a nasal or oral spray.  
     
     
         44 . The composition of  claim 34 ,  35 ,  36 ,  37 , or  38  wherein at least one of the a terfenadine metabolite and the leukotriene inhibitor is administered in an oral solid dosage form.