Novel aerosol formulations of granisetron and uses thereof

Abstract

Aerosol formulations of granisetron 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:
 granisetron 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;   wherein the coarse particle lactose has a D10 of about 3-6 μm, a D90 of about 170 μm, or an average particle size of 40-60 μm;   wherein the fine particle lactose has a D50 of less than 5 μm;   wherein the formulation has a respirable fraction (RPF) of 35% or more, when tested using a Next Generation Impactor (NGI); and   wherein the ratio of granisetron to lactose is about 1:9.   
     
     
         2 . The formulation of  claim 1 , wherein the coarse particle lactose has average particle size of 50 to 60 μm. 
     
     
         3 . The formulation of  claim 1 , wherein the coarse particle lactose has average particle size of 50 or 60 μm. 
     
     
         4 . The formulation of  claim 1 , wherein the coarse particle lactose has average particle size of 55 or 60 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 particle lactose has a D10 of about 4 μm. 
     
     
         7 . The formulation of  claim 1 , wherein the coarse particle lactose has a D90 of about 170 μm. 
     
     
         8 . The formulation of  claim 1 , wherein the fine particle lactose has a D90 of less than 10 μm. 
     
     
         9 . The formulation of  claim 1 , wherein granisetron is about 15% of total composition of the formulation, or about 10% of the total composition of the formulation, or about 5% of the total composition of the formulation. 
     
     
         10 . The formulation of  claim 1 , wherein granisetron is about 15% of total composition. 
     
     
         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 granisetron is more than about 0.1 mg and less than about 10 mg. 
     
     
         13 . The formulation of  claim 1 , wherein granisetron is more than about 0.5 mg and less than about 5 mg. 
     
     
         14 . The formulation of  claim 1 , wherein the mass median aerodynamic diameter (MMAD) of granisetron is between 0.5 and 5 microns. 
     
     
         15 . The formulation of  claim 1 , wherein the mass median aerodynamic diameter (MMAD) of granisetron 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 granisetron in blood plasma that is about 0.8 to 1.05 times of the mean AUC achieved following intravenous bolus delivery of granisetron. 
     
     
         18 . The formulation of  claim 1 , wherein the formulation, when delivered through the pulmonary tract produces a mean area under curve (AUC) of granisetron in blood plasma that is about the same as the mean AUC achieved following intravenous bolus delivery of granisetron. 
     
     
         19 . The formulation of  claim 1 , wherein the formulation, when delivered through the pulmonary tract produces a maximal concentration (Cmax) of granisetron in blood plasma that is about 0.2 to 0.6 times of the mean Cmax achieved following intravenous bolus delivery of granisetron. 
     
     
         20 . The formulation of  claim 1 , wherein the formulation, when delivered through the pulmonary tract produces a maximal concentration (Cmax) of granisetron in blood plasma that is about 0.3 to 0.4 times of the mean Cmax achieved following intravenous bolus delivery of granisetron. 
     
     
         21 . The formulation of  claim 1 , wherein the formulation has a fine particle fraction (FPF) of 11 to 18% as measured by NGI.