Combinations of a muscarinic receptor antagonist and a beta-2 adrenoreceptor agonist

Abstract

Novel combinations of a muscarinic acetylcholine receptor antagonist and a beta 2 agonist for inhaled administration via the nose or mouth, and methods of using them are provided.

1 . A pharmaceutical combination product comprising
 a) a compound of the formula:   
       
         
           
           
               
               
           
         
         wherein 
         X −  is a pharmaceutically acceptable anion; and 
         b) a compound of the formula: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof (Compound (II)). 
       
     
     
         2 . A product according to  claim 1  wherein for Compound (I) the pharmaceutically acceptable anion is selected from the group consisting of chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate or p-toluenesulfonate. 
     
     
         3 . A product according to  claim 1  or  claim 2  wherein Compound (I) is 4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane bromide. 
     
     
         4 . A product according to any of  claims 1  to  3  wherein Compound (II) is 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol α-phenylcinnamate. 
     
     
         5 . A product according to any of  claims 1  to  3  wherein Compound (II) is 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol triphenylacetate. 
     
     
         6 . A product according to any of  claims 1  to  5  wherein Compound (I) and Compound (II) are presented in a form adapted for separate administration. 
     
     
         7 . A product according to any of  claims 1  to  5  wherein Compound (I) and Compound (II) are presented in a form adapted for sequential administration. 
     
     
         8 . A product according to any of  claims 1  to  5  wherein Compound (I) and Compound (II) are presented in a form adapted for simultaneous administration. 
     
     
         9 . A product according to  claim 8  wherein Compound (I) and Compound (II) are in admixture with each other. 
     
     
         10 . A product according to any of  claims 1  to  9  wherein at least one of Compound (I) and Compound (II) is formulated with a pharmaceutically acceptable carrier or excipient. 
     
     
         11 . A product according to any of  claims 1  to  9  in a form suitable for administration by oral or nasal inhalation. 
     
     
         12 . A product according to  claim 11  wherein the form is suitable for administration by inhalation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler. 
     
     
         13 . A product as claimed in  claim 12  wherein each of Compound (I) and Compound (II) is presented in the form of a dry powder composition. 
     
     
         14 . A product as claimed in  claim 13  wherein Compound (I) and Compound (II) are presented as separate compositions. 
     
     
         15 . A product as claimed in  claim 13  wherein Compound (I) and Compound (II) are presented as admixed compositions. 
     
     
         16 . A product as claimed in  claim 14  or  15  wherein at least one of said compositions of Compound (I) or Compound (II) contains a carrier. 
     
     
         17 . A product as claimed in  claim 14  or  15  wherein both compositions of Compound (I) and Compound (II) contain a carrier. 
     
     
         18 . A product as claimed in  claim 16  or  17  wherein the carrier is lactose. 
     
     
         19 . A product as claimed in any of  claims 13  to  18  wherein at least one of said compositions contains a ternary agent. 
     
     
         20 . A product as claimed in any of  claims 13  to  18  wherein both compositions contain a ternary agent. 
     
     
         21 . A product as claimed in  claim 19  wherein the ternary agent is magnesium stearate. 
     
     
         22 . A product as claimed in  claim 20 , wherein the ternary agent in both compositions is magnesium stearate. 
     
     
         23 . A product as claimed in  claim 22 , wherein magnesium stearate is present in an amount of about 0.6% w/w in a composition of Compound (I), and/or an amount of about 1.0% w/w in a composition of Compound (II). 
     
     
         24 . A product as claimed in any one of  claims 13  to  23  wherein said separate or admixed compositions are in unit dose form. 
     
     
         25 . A product as claimed in  claim 24  wherein the unit dose form is in a capsule, cartridge or blister pack. 
     
     
         26 . A product as claimed in any of  claims 13  to  25  wherein the composition is administered via a dry powder inhaler. 
     
     
         27 . A product as claimed in  claim 26  wherein said inhaler permits separate containment of the active ingredients. 
     
     
         28 . A product as claimed in any one of  claims 1  to  27  wherein Compound (I) is present in an amount of about 1 to 1000 mcg/dose. 
     
     
         29 . A product as claimed in any one of  claims 1  to  27  wherein Compound (I) is present in an amount of 125 mcg/dose. 
     
     
         30 . A product as claimed in any one of  claims 1  to  27  wherein Compound (I) is present in an amount of 62.5 mcg/dose. 
     
     
         31 . A product according to any one of  claims 1  to  30  wherein Compound (II) is present in an amount of 1 to 100 mcg/dose. 
     
     
         32 . A product according to any one of  claims 1  to  30  wherein Compound (II) is present in an amount of 25 mcg/dose. 
     
     
         33 . A dry powder inhaler containing a product as defined in any of  claims 1  to  32 . 
     
     
         34 . A product according to  claim 11  wherein each of Compound (I) and Compound (II) is presented in the form of a spray composition for inhalation. 
     
     
         35 . A product according to  claim 34  wherein Compound (I) and Compound (II) are presented as separate or admixed compositions. 
     
     
         36 . A product according to  claim 34  or  claim 35  wherein the spray composition is an aqueous solution or suspension. 
     
     
         37 . A product according to  claim 34  or  35  wherein the spray composition is an aerosol composition. 
     
     
         38 . A product according to  claim 37  comprising as propellant a fluorocarbon or hydrogen-containing chlorofluorocarbon. 
     
     
         39 . A product according to  claim 38  wherein the propellant is a hydrofluoroalkane. 
     
     
         40 . A product according to  claim 39  wherein the propellant is 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. 
     
     
         41 . A product according to any of  claims 34  to  40  further comprising a co-solvent. 
     
     
         42 . A product according to any of  claims 34  to  41  further comprising a surface-active agent. 
     
     
         43 . A product according to any of  claims 1  to  42  further comprising an inhaled corticosteroid selected from the group consisting of fluticasone propionate, mometasone furoate, budesonide and 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate). 
     
     
         44 . A product according to  claim 43  wherein the inhaled corticosteroid is 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate). 
     
     
         45 . A product according to  claim 44 , wherein 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate) is present in an amount of 100 mcg/dose. 
     
     
         46 . A pressurised metered dose inhaler containing a product as defined in any of  claims 1  to  11  and  34  to  45 . 
     
     
         47 . Use of the product as defined in any of  claims 1  to  32  and  34  to  45  in the manufacture of a medicament for the prophylaxis or treatment of conditions for which administration of one or more of Compound (I) and Compound (II) is indicated. 
     
     
         48 . The use according to  claim 47 , for the treatment of inflammatory or respiratory tract diseases, by simultaneous or sequential administration, in any order, of Compound (I) and Compound (II). 
     
     
         49 . The use according to  claim 47  or  48 , for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease (COPD) and/or asthma by simultaneous or sequential administration of Compound (I) and Compound (II). 
     
     
         50 . A method for the prophylaxis or treatment of inflammatory or respiratory tract diseases, comprising administering to a patient in need thereof, a product as defined in to any of  claims 1  to  32  and  34  to  45 . 
     
     
         51 . A method according to  claim 50  wherein the active ingredients of said product are administered either sequentially or simultaneously. 
     
     
         52 . A method according to  claim 50  or  51  wherein the disease is selected from the group consisting of chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, allergic rhinitis, small airways disease, bronchiectasis and cystic fibrosis. 
     
     
         53 . A method according to  claim 52  wherein the disease is chronic obstructive lung disease (COPD). 
     
     
         54 . A method according to  claim 53  for the treatment of chronic obstructive pulmonary disease (COPD), by simultaneous or sequential administration of the active ingredients of a product as defined in any of  claims 1  to  32  and  34  to  45 . 
     
     
         55 . A method according to any of  claims 50  to  54  wherein administration is via inhalation by the mouth or nose. 
     
     
         56 . A method according to  claim 55  wherein administration is via a medicament dispenser selected from a reservoir dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler. 
     
     
         57 . The method according to any of  claims 50  to  56  wherein the product is administered once per day. 
     
     
         58 . A product as defined in any of  claims 1  to  32  and  34  to  45  for use in the treatment of inflammatory or respiratory tract diseases, by simultaneous or sequential administration, in any order, of Compound (I) and Compound (II). 
     
     
         59 . A product according to  claim 58  for use in the treatment of chronic obstructive pulmonary disease (COPD) and/or asthma by simultaneous or successive administration of Compound (I) and Compound (II). 
     
     
         60 . A dry powder inhaler comprising two compositions presented separately, wherein the first composition comprises
 i. 4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane bromide, and   ii. lactose, and   iii. magnesium stearate at an amount of about 0.6% w/w based on the total weight of the first composition;   
       and the second composition comprises
 iv. 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol triphenylacetate, and 
 v. lactose, and 
 vi. magnesium stearate at an amount of about 1.0% w/w based on the total weight of the second composition. 
 
     
     
         61 . A dry powder inhaler according to  claim 60 , wherein each composition is in unit dose form. 
     
     
         62 . A dry powder inhaler according to  claim 61 , wherein the unit dose form is a capsule, cartridge or blister. 
     
     
         63 . A dry powder inhaler according to  claim 61  or  62  wherein 4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane bromide is present in an amount of about 125 mcg/dose. 
     
     
         64 . A dry powder inhaler according to  claim 61  or  62  wherein 4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane bromide is present in an amount of about 62.5 mcg/dose. 
     
     
         65 . A dry powder inhaler according to any of  claims 61  to  64  wherein 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol triphenylacetate is present in an amount of about 25 mcg/dose. 
     
     
         66 . A dry powder inhaler according to  claim 60  wherein the second composition further comprises 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate). 
     
     
         67 . A dry powder inhaler according to  claims 61  to  65  wherein the second composition further comprises 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate). 
     
     
         68 . A dry powder inhaler according to  claim 67  wherein 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (fluticasone furoate) is present in an amount of about 100 mcg/dose.