Aerosol tyrosine kinase inhibitor compounds and uses thereof

Abstract

Disclosed herein are formulations of imatinib or a phenylaminopyrimidine derivative compound for aerosolization and use of such formulations for inhaled aerosol administration of imatinib or a phenylaminopyrimidine derivative compound for the prevention or treatment of various fibrotic, carcinogenic, vascular and viral infectious diseases, including diseases associated with the lung, heart, kidney, liver, eye, central nervous system and surgical sites. In some embodiments, formulations and delivery options described herein allow for efficacious local delivery of imatinib or a phenylaminopyrimidine derivative compound or salt thereof. Compositions include all formulations, kits, and device combinations described herein. Methods include inhalation procedures, indications and manufacturing processes for production and use of the compositions described. Also included are methods for identifying compounds and indications that may benefit by reformulation and inhalation administration.

What is claimed is: 
     
         1 . An aqueous solution for nebulized inhalation administration comprising: water; imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof, at a concentration from about 0.001 mg/mL to about 200 mg/mL; wherein the osmolality of the aqueous solution is from about 50 mOsmol/kg to about 2000 mOsmol/kg. 
     
     
         2 . The aqueous solution of  claim 1 , wherein:
 the solution further comprises one or more additional ingredients selected from co-solvents, tonicity agents, sweeteners, surfactants, wetting agents, chelating agents, anti-oxidants, inorganic salts, and buffers.   
     
     
         3 . The aqueous solution of  claim 2 , wherein:
 the buffer is a citrate buffer or phosphate buffer; and   the inorganic salt is sodium chloride, sodium bromide or magnesium chloride.   
     
     
         4 . The solution of  claim 1 , wherein the aqueous solution comprises:
 water;   imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof at a concentration from about 0.001 mg/mL to about 200 mg/mL;   optionally a phosphate buffer that maintains the pH of the solution from about pH 4.0 to about pH 8.0 or a citrate buffer that maintains the pH of the solution from about pH 4.0 to about pH 7.0;   optionally sodium saccharin at a concentration of about 0.01 mM to about 10 mM;   wherein the osmolality of the of the aqueous solution is from about 50 mOsmol/kg to about 2000 mOsmol/kg.   
     
     
         5 . The solution of  claim 1 , wherein the aqueous solution comprises:
 water;   imatinib phosphate at a concentration from about 0.001 mg/mL to about 200 mg/mL;   wherein the osmolality of the of the aqueous solution is from about 50 mOsmol/kg to about 2000 mOsmol/kg.   
     
     
         6 . A method for the treatment of lung disease in a mammal comprising:
 administering a pharmaceutical composition comprising imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or tyrosine kinase inhibitor or salt thereof compound by inhalation to the mammal in need thereof.   
     
     
         7 . The method of  claim 6 , wherein:
 the pharmaceutical composition comprising imatinib or salt thereof, phenylaminopyrimidine derivative or salt thereof, or tyrosine kinase inhibitor or salt thereof is administered with a nebulizer, a metered dose inhaler, or a dry powder inhaler.   
     
     
         8 . The of  claim 7 , wherein the pharmaceutical composition comprising imatinib or salt thereof, phenylaminopyrimidine derivative or salt thereof, or tyrosine kinase inhibitor or salt thereof is an aqueous solution and is administered to the mammal with a liquid nebulizer;
 wherein the aqueous solution comprises water; imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof, at a concentration from about 0.001 mg/mL to about 200 mg/mL; wherein the osmolality of the aqueous solution is from about 50 mOsmol/kg to about 2000 mOsmol/kg.   
     
     
         9 . The method of  claim 8 , wherein:
 the liquid nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer comprising a vibrating mesh or plate with multiple apertures, or a nebulizer comprising a vibration generator and an aqueous chamber.   
     
     
         10 . The method of  claim 9 , wherein the liquid nebulizer:
 (i) achieves lung deposition of at least 7% of the imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof administered to the mammal;   (ii) provides a Geometric Standard Deviation (GSD) of emitted droplet size distribution of the aqueous solution of about 1.0 μm to about 2.5 μm;   (iii) provides: a) a mass median aerodynamic diameter (MMAD) of droplet size of the aqueous solution emitted with the high efficiency liquid nebulizer of about 1 μm to about 5 μm;
 b) a volumetric mean diameter (VMD) of about 1 μm to about 5 μm; 
 and/or 
 c) a mass median diameter (MMD) of about 1 μm to about 5 μm; 
   (iv) provides a fine particle fraction (FPF=%≦5 microns) of droplets emitted from the liquid nebulizer of at least about 30%;   (v) provides an output rate of at least 0.1 mL/min; and/or   (vi) provides at least about 25% of the aqueous solution to the mammal.   
     
     
         11 . The method of  claim 8 , wherein:
 the liquid nebulizer delivers from about 0.001 mg to about 200 mg of imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof compound to the lungs of the mammal in less than about 20 minutes with mass median diameter (MMAD) particles sizes from about 1 to about 5 micron.   
     
     
         12 . The method of  claim 8 , wherein the pharmaceutical composition comprises from about 0.1 mL to about 6 mL of an aqueous solution comprising imatinib or salt thereof or a phenylaminopyrimidine derivative compound or salt thereof, or tyrosine kinase inhibitor compound or salt thereof, and optionally one or more additional ingredients selected from co-solvents, tonicity agents, sweeteners, surfactants, wetting agents, chelating agents, anti-oxidants, inorganic salts, and buffers, wherein the concentration of imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or tyrosine kinase inhibitor compound or salt thereof in the aqueous solution is from about 0.001 mg/mL and about 200 mg/mL and the osmolality of the of the aqueous solution is from about 50 mOsmol/kg to about 2000 mOsmol/kg. 
     
     
         13 . The method of  claim 12 , wherein the aqueous solution comprises:
 water;   imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor compound or salt thereof at a concentration from about 0.001 mg/mL to about 200 mg/mL;   optionally one or more inorganic salts selected from the group consisting of sodium chloride, magnesium chloride, sodium bromide, magnesium bromide, calcium chloride and calcium bromide, wherein the total amount of the one or more inorganic salts is from about 0.01% to about 2.0% by weight of the weight of aqueous solution;   optionally a phosphate buffer that maintains the pH of the solution from about pH 5.0 to about pH 8.0, or citrate buffer than maintains the pH of the solution from about 4.0 to about 7.0;   optionally sodium saccharin at a concentration of about 0.01 mM to about 10 mM;   wherein the osmolality of the aqueous solution is from about 50 mOsmol/kg to about 2000 mOsmol/kg.   
     
     
         14 . The method of  claim 6 , wherein:
 the pharmaceutical composition comprises a dry powder composition comprising imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof at a concentration of about 0.001% to about 100% by weight of the weight of dry powder composition; optionally one of more carrier agents selected from the group consisting of lactose or mannitol at a concentration of about 0.001% to about 99.999% by weight of the weight of dry powder composition; and optionally sodium saccharin at a concentration of about 0.001% to about 0.1% by weight of the weight of dry powder composition;   wherein the pharmaceutical composition is administered to the mammal with a dry powder inhaler.   
     
     
         15 . The method of  claim 14 , wherein the dry powder inhaler delivers from about 0.001 mg to about 200 mg of imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof to the lungs of the mammal in less than about 10 breaths, wherein the mass median diameter (MMAD) particles sizes are from about 1 to about 5 micron. 
     
     
         16 . The method of  claim 6 , wherein:
 the pharmaceutical composition comprises imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof, wherein the total amount of imatinib or salt thereof, phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof is about 0.001% to about 10% by volume of the volume of the pharmaceutical composition; one or more propellants, wherein the total amount of the one or more propellants is about 90% to about 99.999% by volume of the volume of the pharmaceutical composition;   optionally one of more cosolvents selected from the group consisting of ethanol and propylene glycol, wherein the total amount of the one or more cosolvents is from about 0.01% to about 10% by volume of the volume of the pharmaceutical composition;   wherein the pharmaceutical composition is administered to the mammal with a metered dose inhaler.   
     
     
         17 . The method of  claim 16 , wherein the meter dose inhaler delivers from about 0.001 mg to about 200 mg of imatinib or salt thereof, a phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof to the lungs of the mammal in less than about 10 breaths, wherein the mass median diameter (MMAD) particles sizes are from about 1 to about 5 micron. 
     
     
         18 . The method of  claim 6 , wherein the lung disease is lung fibrosis, lung cancer, or pulmonary hypertension, and the mammal is a human. 
     
     
         19 . The method of  claim 6 , wherein the pharmaceutical composition comprising imatinib or salt thereof, phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof is administered to the mammal in need thereof by inhalation on a continuous dosing schedule. 
     
     
         20 . The method of  claim 19 , wherein the pharmaceutical composition comprising imatinib or salt thereof, phenylaminopyrimidine derivative or salt thereof, or other tyrosine kinase inhibitor or salt thereof is administered once a week, twice a week, three times a week, four times a weeks, five times a week, six times a week, seven days a week, once a day, twice a day, three times a day, four times a day, five times a day, or six times a day. 
     
     
         21 . A crystalline salt of imatinib, wherein the crystalline salt is a crystalline phosphate salt of imatinib, crystalline fumarate salt of imatinib, or crystalline hydrochloride salt of imatinib. 
     
     
         22 . The crystalline salt of  claim 21 , wherein the crystalline salt is a crystalline phosphate salt of imatinib that is characterized as having:
 an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in  FIG. 4 ;   an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.71° 2-Theta, 7.34° 2-Theta, 10.04° 2-Theta, 10.98° 2-Theta, 16.75° 2-Theta, 22.03° 2-Theta, 23.53° 2-Theta, 33.30° 2-Theta, and 33.88° 2-Theta;   an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in  FIG. 5 ;   an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.68° 2-Theta, 7.34° 2-Theta, 10.99° 2-Theta, 14.65° 2-Theta, 14.81° 2-Theta, 18.35° 2-Theta, 22.05° 2-Theta, 24.85° 2-Theta, and 33.35° 2-Theta;   an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in  FIG. 6 ;   or   an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.13° 2-Theta, 7.55° 2-Theta, 8.93° 2-Theta, 14.08° 2-Theta, 17.28° 2-Theta, 17.82° 2-Theta, 18.86° 2-Theta, 19.89° 2-Theta, 21.06° 2-Theta, 21.67° 2-Theta, 23.93° 2-Theta, 24.35° 2-Theta, 24.66° 2-Theta, and 25.32° 2-Theta.   
     
     
         23 . The crystalline salt of  claim 21 , wherein the crystalline salt is a crystalline fumarate salt of imatinib that is characterized as having:
 an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in  FIG. 2 ;   or   an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.05° 2-Theta, 11.91° 2-Theta, 16.04° 2-Theta, 16.27° 2-Theta, 17.38° 2-Theta, 19.98° 2-Theta, 20.88° 2-Theta, 23.78° 2-Theta, 24.51° 2-Theta, 25.84° 2-Theta, 26.73° 2-Theta, and 28.92° 2-Theta.   
     
     
         24 . The crystalline salt of  claim 21 , wherein the crystalline salt is a crystalline hydrochloride salt of imatinib that is characterized as having:
 an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in  FIG. 3 ;   or   an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.68° 2-Theta, 9.78° 2-Theta, 13.28° 2-Theta, 16.46° 2-Theta, 16.94° 2-Theta, 19.93° 2-Theta, 22.35° 2-Theta, 22.58° 2-Theta, 23.24° 2-Theta, 23.50° 2-Theta, 26.42° 2-Theta and 29.66° 2-Theta.