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 formulation, comprising:
 ondansetron having a mass median aerodynamic diameter of between 0.05 and 20 microns; and   optionally at least one selected from the group consisting of a pharmaceutically acceptable excipient and a propellant,   wherein the excipient is selected from the group consisting of a carbohydrate, an amino acid, a polypeptide, a lipid, a salt, a polyalcohol, an oleate, a stearate, a myristate, an alkylether, an alkyl arylether, and a sorbate.   
     
     
         2 . The formulation of  claim 1 , wherein the pharmaceutically acceptable excipient is present and comprises galactose, mannose, sorbose, lactose, glucose, trehalose, raffinose, maltodextrins, dextrans, mannitol, xylitol, or any mixture thereof. 
     
     
         3 . The formulation of  claim 2 , wherein the pharmaceutically acceptable excipient is lactose, glucose, or a mixture thereof. 
     
     
         4 . The formulation of  claim 1 , wherein the propellant is present and comprises 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n propane, or a mixture thereof. 
     
     
         5 . The formulation of  claim 4 , wherein the pharmaceutically acceptable excipient is present and comprises an oleate, a stearate, a myristate, an alkylether, an alkyl arylether, a sorbate, or any mixtures thereof. 
     
     
         6 . The formulation of  claim 5 , wherein the pharmaceutically acceptable excipient is sorbitan trioleate, isopropyl myristate, or a mixture thereof. 
     
     
         7 . The formulation of  claim 4 , further comprising:
 a cosolvent, which is C 2-6  alcohol, polyols, cineole, citral, lactic acid oligomers, poly(ethylene glycols), or a mixture thereof.   
     
     
         8 . The formulation of  claim 1 , wherein the ondansetron has a mean geometric diameter between 0.05 and 20 microns. 
     
     
         9 . The formulation of  claim 1 , wherein the mass median aerodynamic diameter of the ondansetron is from 0.5 to 5 microns. 
     
     
         10 . The formulation of  claim 9 , wherein the proportion of ondansetron particles with aerodynamic diameters less than 5 μm is from 70% to 100%. 
     
     
         11 . The formulation of  claim 9 , wherein the proportion of ondansetron particles with aerodynamic diameters less than 5 μm is from 10% to 70%. 
     
     
         12 . The formulation of  claim 2 , wherein the pharmaceutically acceptable excipient comprises a powder having an average particle size of <5 to 200 microns. 
     
     
         13 . The formulation of  claim 12 , wherein the pharmaceutically acceptable excipient is a mixture of a first excipient powder having an average particle size from <5 to 50 microns and a second excipient powder having an average particles size of 50 to 200 microns. 
     
     
         14 . The formulation of  claim 13 , wherein the first excipient powder and the second excipient powder are each independently lactose or glucose. 
     
     
         15 . The formulation of  claim 14 , wherein formulation contains 0.1-40 mg of the powdered ondansetron and from 0.001-2.5 g of the lactose and/or glucose. 
     
     
         16 . The formulation of  claim 4 , wherein formulation contains 0.1-400 mg of the ondansetron and from 0.5-50 g of the 1,1,1,2-tetrafluoroethane and/or 1,1,1,2,3,3,3-heptafluoro-n propane. 
     
     
         17 . The formulation of  claim 1 , wherein the amount of the ondansetron in the formulation is from 0.01 to 100 wt %, based on the total weight of the formulation. 
     
     
         18 . The formulation of  claim 17 , wherein the formulation is a dry powder formulation and the amount of the ondansetron in the formulation is from 0.05 to 100 wt %, based on the total weight of the formulation. 
     
     
         19 . The formulation of  claim 17 , wherein the formulation is a pMDI formulation and the amount of the ondansetron in the formulation is from 0.01 to 20 wt %, based on the total weight of the formulation. 
     
     
         20 . The formulation of  claim 1 , wherein the ondansetron has respirable fraction of 15% or more. 
     
     
         21 . 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.   
     
     
         22 . The method of  claim 21 , wherein from 0.1 mg to 40 mg of ondansetron are administered. 
     
     
         23 . The method of  claim 21 , wherein a total dosage of ondansetron is from 0.1 mg to 40 mg per day. 
     
     
         24 . The method of  claim 21 , wherein the administration provides at least one of the following:
 a maximum ondansetron concentration (Cmax) in plasma from 1 ng/mL to 5000 ng/mL;   a maximum concentration in the plasma ondansetron reaches at (Tmax) from 1 minute to 2 hours; and   an area under curve (AUC) of ondansetron in blood plasma from 2 ng*h/mL to 50000 ng*h/mL.