Novel aerosol formulations of ondansetron and uses thereof

Abstract

Aerosol formulations of ondansetron useful for pulmonary delivery are provided. The formulations are useful in the reduction, elimination or prevention of nausea and vomiting associated with chemotherapy, radiation therapy, and surgery. Also provided are novel methods to treat chemotherapy-induced nausea and vomiting (CINV), radiation-induced nausea and vomiting (RINV), and post-operative nausea and vomiting (PONV) using the inhalation formulations.

1 . A dry powder aerosol formulation for use in a dry powder inhaler, comprising:
 ondansetron having a mean geometric diameter of between 1-3 microns; and a pharmaceutically acceptable excipient   wherein the excipient is a mixture of coarse and fine particle lactose;   and the coarse particle lactose has a D10 of about 3-6 μm, or a D90 of about 170 μm or has an average particle size of 50-200 μm;   the fine particle lactose has a D50 of less than 5 μm; and   the formulation has a respirable fraction (RPF) of 50% or more, when tested using a Next Generation Impactor (NGI).   
     
     
         2 . The formulation of  claim 1 , wherein the coarse lactose particle has average particle size of 50 to 90 μm. 
     
     
         3 . The formulation of  claim 1 , wherein the coarse lactose particle has average particle size of 50 to 60 or 65 to 85 μm. 
     
     
         4 . The formulation of  claim 1 , wherein the coarse lactose particle has average particle size of 70 to 80 μm. 
     
     
         5 . A method of treating nausea or vomiting, the method comprising:
 administering the formulation of  claim 1  to a subject in need thereof, wherein the formulation is administered into the pulmonary tract of the subject by inhalation   
     
     
         6 . The formulation of  claim 1 , wherein the coarse lactose particle has a D10 of about 4 μm. 
     
     
         7 . The formulation of  claim 1 , wherein the coarse lactose particle has a D90 of about 170 μm. 
     
     
         8 . The formulation of  claim 1 , wherein the fine lactose particle has a D90 of less than 10 μm. 
     
     
         9 . The formulation of  claim 1 , wherein ondansetron is about 30% of total composition of the formulation, or about 15% of the total composition of the formulation, or about 10% of the total composition of the formulation. 
     
     
         10 . The formulation of  claim 1 , wherein the ratio of ondansetron to lactose is about 1:9. 
     
     
         11 . The formulation of  claim 1 , wherein the ratio of coarse to fine lactose is about 9:1 
     
     
         12 . The formulation of  claim 1 , wherein ondansetron is more than about 1 mg and less than about 20 mg. 
     
     
         13 . The formulation of  claim 1 , wherein ondansetron is more than about 2 mg and less than about 10 mg. 
     
     
         14 . The formulation of  claim 1 , wherein the mass median aerodynamic diameter (MMAD) of ondansetron is between 0.5 and 5 microns. 
     
     
         15 . The formulation of  claim 1 , wherein the mass median aerodynamic diameter (MMAD) of ondansetron is at least 2 microns; and at most 3.5 microns. 
     
     
         16 . The formulation of  claim 1 , wherein the formulation has a fine particle fraction (FPF) of at least 55%, when tested using a Next Generation Impactor (NGI). 
     
     
         17 . The formulation of  claim 1 , wherein the formulation, when delivered through the pulmonary tract produces a mean area under curve (AUC) of ondansetron in blood plasma that is about 0.8 to 1.05 times of the mean AUC achieved following intravenous bolus delivery of ondansetron. 
     
     
         18 . The formulation of  claim 1 , wherein the formulation, when delivered through the pulmonary tract produces a mean area under curve (AUC) of ondansetron in blood plasma that is about the same as the mean AUC achieved following intravenous bolus delivery of ondansetron. 
     
     
         19 . The formulation of  claim 1 , wherein the formulation, when delivered through the pulmonary tract produces a maximal concentration (Cmax) of ondansetron in blood plasma that is about 0.2 to 0.6 times of the mean Cmax achieved following intravenous bolus delivery of ondansetron. 
     
     
         20 . The formulation of  claim 1 , wherein the formulation, when delivered through the pulmonary tract produces a maximal concentration (Cmax) of ondansetron in blood plasma that is about 0.3 to 0.4 times of the mean Cmax achieved following intravenous bolus delivery of ondansetron.