Pde5 inhibitor powder formulations and methods relating thereto

Abstract

Novel dry powder compositions comprising and methods relating thereto are provided. The dry powder compositions comprise PDE5 inhibitors, such as vardenafil, or pharmaceutically acceptable salts or esters thereof. The dry powder compositions may optionally include an carrier/excipient. The concentration of active agent may be at least about 2% by weight. Methods of aerosolizing the dry powder compositions and using them to treat various diseases are also disclosed.

1 . A powder pharmaceutical composition comprising a) at least about 2% by weight of a PDE5 inhibitor or a pharmaceutically acceptable salt or ester thereof relative to the total weight of the overall pharmaceutical composition, and b) at least one pharmaceutically acceptable carrier. 
     
     
         2 . The powder pharmaceutical composition of  claim 1 , wherein the PDE5 inhibitor is at least one of vardenafil, sildenafil, tadalafil, avanafil, benzamidenafil, lodenafil, mirodenafil, udenafil, or zaprinast, or a pharmaceutically acceptable salt or ester thereof. 
     
     
         3 . The powder pharmaceutical composition of  claim 1 , wherein the composition comprises at least about 2% to about 20% by weight of the PDE5 inhibitor. 
     
     
         4 . The powder pharmaceutical composition of  claim 1 , wherein the composition comprises at least about 2% to about 20% by weight of vardenafil or a pharmaceutically acceptable salt or ester thereof. 
     
     
         5 . The powder pharmaceutical composition of  claim 1 , wherein the at least one pharmaceutically acceptable carrier comprises lactose, mannitol, trehalose, or starch. 
     
     
         6 . The powder pharmaceutical composition of  claim 5 , wherein the at least one pharmaceutically acceptable carrier comprises at least one of a mono-, di- or polysaccharide, or their derivatives, calcium stearate, magnesium stearate, leucine or its derivatives, lecithin, human serum albumin, polylysine, polyarginine, or other force control agents, or combinations thereof. 
     
     
         7 . The powder pharmaceutical composition of  claim 1 , wherein the PDE5 inhibitor or a pharmaceutically acceptable salt or ester is micronized. 
     
     
         8 . The powder pharmaceutical composition of  claim 1 , wherein the composition is packaged to have a nominal load of about 3 mg to 30 mg. 
     
     
         9 . The powder pharmaceutical composition of  claim 1 , wherein the composition is packaged to have a nominal dose of at least about 0.25 mg. 
     
     
         10 . The powder pharmaceutical composition of  claim 1 , wherein the composition is packaged to have a delivered dose of at least about 0.075 mg. 
     
     
         11 . A method of aerosolizing a powder pharmaceutical composition comprising a) at least 2% by weight of a PDE5 inhibitor, or a pharmaceutically acceptable salt or ester thereof, relative to the total weight of the overall pharmaceutical composition, and b) at least one pharmaceutically acceptable carrier, the method comprising:
 providing an inhaler comprising a dispersion chamber having an inlet and an outlet, the dispersion chamber containing an actuator that is movable reciprocatable along a longitudinal axis of the dispersion chamber; and   inducing air flow through the outlet channel to cause air and the powder pharmaceutical composition to enter into the dispersion chamber from the inlet, and to cause the actuator to oscillate within the dispersion chamber to assist in dispersing the powder   pharmaceutical composition from the outlet for delivery to a subject through the outlet.   
     
     
         12 . The method of  claim 11 , wherein the PDE5 inhibitor is at least one of vardenafil, sildenafil, tadalafil, avanafil, benzamidenafil, lodenafil, mirodenafil, udenafil, or zaprinast, or a pharmaceutically acceptable salt or ester thereof. 
     
     
         13 . The method of  claim 11 , wherein the composition comprises at least about 2% to about 20% by weight of the PDE5 inhibitor. 
     
     
         14 . The method of  claim 11 , wherein the composition comprises at least about 2% to about 20% by weight of vardenafil or a pharmaceutically acceptable salt or ester thereof. 
     
     
         15 . The method of  claim 11 , wherein the at least one pharmaceutically acceptable carrier comprises lactose, mannitol, trehalose, or starch. 
     
     
         16 . The method of  claim 11 , wherein the at least one pharmaceutically acceptable carrier comprises at least one of a mono-, di- or poly-saccharide, or their derivatives, calcium stearate, magnesium stearate, leucine or its derivatives, lecithin, human serum albumin, polylysine, polyarginine, or other force control agents, or combinations thereof. 
     
     
         17 . The method of  claim 11 , wherein the composition has a mass median aerodynamic diameter of between 0.5 μm and 5 μm upon aerosolization. 
     
     
         18 . The method of  claim 11 , wherein the composition has a fine particle fraction of at least about 20% upon aerosolization. 
     
     
         19 . The method of  claim 11 , wherein the composition has an emitted dose of at least about 40% upon aerosolization. 
     
     
         20 . The method of  claim 11 , wherein the powdered medicament is stored within a storage compartment, and wherein the powder pharmaceutical composition is transferred from the storage compartment, through the inlet and into the dispersion chamber. 
     
     
         21 . The method of  claim 11 , wherein the inlet is in fluid communication with an initial chamber, and wherein the powder pharmaceutical composition is received into the initial chamber prior to passing through the inlet and into the dispersion chamber. 
     
     
         22 . A method of treating a disease in a subject in need thereof, the method comprising administering to the subject via a pulmonary route an effective amount of a powder pharmaceutical composition comprising a) at least about 2% of a PDE5 inhibitor, or a pharmaceutically acceptable salt or ester thereof, by weight relative to the total weight of the overall pharmaceutical composition dose, and b) at least one pharmaceutically acceptable carrier. 
     
     
         23 . The method of  claim 22 , wherein the disease is a lung disease or a heart disease. 
     
     
         24 . The method of  claim 23 , wherein the lung disease is pulmonary hypertension or cystic fibrosis. 
     
     
         25 . The method of  claim 23 , wherein the heart disease is congestive heart failure. 
     
     
         26 . The method of  claim 22 , wherein the powder pharmaceutical composition is administered as an aerosol. 
     
     
         27 . The method of  claim 22 , wherein the powder pharmaceutical composition is administered using a dry powder inhaler or a metered dose inhaler. 
     
     
         28 . The method of  claim 22 , wherein the powder pharmaceutical composition is administered by
 providing an inhaler comprising a dispersion chamber having an inlet and an outlet, the dispersion chamber containing an actuator that is movable reciprocatable along a longitudinal axis of the dispersion chamber; and   inducing air flow through the outlet channel to cause air and the powder pharmaceutical composition to enter into the dispersion chamber from the inlet, and to cause the actuator to oscillate within the dispersion chamber to assist in dispersing the powder pharmaceutical composition from the outlet for delivery to a subject through the outlet.   
     
     
         29 . The method of  claim 22 , wherein the PDE5 inhibitor is at least one of vardenafil, sildenafil, tadalafil, avanafil, benzamidenafil, lodenafil, mirodenafil, udenafil, or zaprinast, or a pharmaceutically acceptable salt or ester thereof. 
     
     
         30 . The method of  claim 22 , wherein the composition comprises at least about 2% to about 20% by weight of the PDE5 inhibitor. 
     
     
         31 . The method of  claim 22 , wherein the composition comprises at least about 2% to about 20% by weight of vardenafil or a pharmaceutically acceptable salt or ester thereof. 
     
     
         32 . The method of  claim 22 , wherein the composition further comprises at least one pharmaceutically acceptable salt, and wherein the at least one pharmaceutically acceptable carrier comprises lactose, mannitol, trehalose, or starch. 
     
     
         33 . The method of  claim 22 , wherein the composition further comprises at least one pharmaceutically acceptable salt, and wherein the at least one pharmaceutically acceptable carrier comprises at least one of a mono-, di- or poly-saccharide, or their derivatives, calcium stearate, magnesium stearate, leucine or its derivatives, lecithin, human serum albumin, polylysine, polyarginine, or other force control agents, or combinations thereof. 
     
     
         34 . The method of  claim 22 , wherein a delivered dose of about 0.25 mg to about 20 mg is delivered to the subject upon aerosolization.