Aerosol Formulations Comprising Formoterol Fumarate Dihydrate

Abstract

A pharmaceutical aerosol formulation comprising formoterol fumarate di-hydrate in suspension, and a steroid in suspension, and a propellant, ethanol, and optionally a surfactant, wherein the formoterol fumarate di-hydrate has a water content of about 4.8 to 4.28% by weight.

1 . A pharmaceutical aerosol formulation for use in a metered dose inhaler (MDI) comprising formoterol fumarate di-hydrate in suspension, a propellant and ethanol, wherein the formoterol fumarate di-hydrate has a water content of about 4.8 to 4.28% by weight.  
   
   
       2 . The pharmaceutical aerosol formulation according to  claim 1  further comprising a steroid in solution.  
   
   
       3 . The pharmaceutical aerosol suspension formulation according to  claim 2 , wherein the formulation is capable of being dispensed from an MDI to provide a Delivered dose of formoterol fumarate di-hydrate that has a variance of no more than +/−25%, of the mean Delivered dose when the formulation is stored at 40° C. and 75% relative humidity for up to 6 months.  
   
   
       4 . The pharmaceutical aerosol suspension formulation according to  claim 2 , wherein the formulation is capable of being dispensed from an MDI to provide a Delivered dose of formoterol fumarate di-hydrate with a fine particle fraction of 30 to 70%.  
   
   
       5 . The pharmaceutical aerosol suspension formulation according to  claim 2 , wherein the formoterol fumarate di-hydrate is provided as particles having a water content of about 4.8 to 4.28% by weight suspended in the propellant and solvent, and wherein the formulation is capable of being dispensed from an MDI to provide a Delivered dose of the steroid that has a variance of no more than +/−25%, of the mean Delivered dose when the formulation is stored at 40° C. and 75% relative humidity for up to 6 months.  
   
   
       6 . The pharmaceutical aerosol suspension formulation according to  claim 5 , wherein the formulation is capable of being dispensed from an MDI to provide a Delivered dose of steroid containing a fine particle fraction of 30% to 70%.  
   
   
       7 . The formulation according to  claim 2 , wherein the steroid is selected from the group consisting of budesonide, ciclesonide, mometasone, fluticasone, beclomethasone, flunisolide, loteprednol, triamcinolone, amiloride, rofleponide or a pharmaceutically acceptable salt or derivative of these active compounds, selected from mometasone furoate, fluticasone dipropionate, beclomethasone dipropionate, triamcinolone acetonide and flunisolide acetate.  
   
   
       8 . The formulation according to  claim 7  wherein the steroid is fluticasone propionate.  
   
   
       9 . The formulation according to  claim 8  wherein the fluticasone proprionate is present in an amount of 0.05 to 2% by weight of the formulation.  
   
   
       10 . The formulation according to  claim 1  or  claim 2 , wherein the formoterol fumarate di-hydrate is present in an amount of 0.001 to 0.1% by weight of the formulation.  
   
   
       11 . The formulation according to according to  claim 1  or  claim 2  containing a cromone selected from the group consisting of a pharmaceutically acceptable salt of cromoglycinic acid, nedocromil, and mixtures thereof.  
   
   
       12 . The formulation according to  claim 11  wherein the cromone is present in the formulation in an amount of 0.001 to 1%.  
   
   
       13 . The formulation according to  claim 1  or  claim 2 , wherein the propellant is selected from the group consisting of fluorochlorocarbons, alkanes, fluorinated alkanes, and hydrofluoroalkanes.  
   
   
       14 . The formulation according to  claim 13  wherein the propellant is a hydrofluoroalkane of the general formula:  
       C x H y F z   (I);  
     in which x is the number 1, 2 or 3, y and z are each an integer greater than or equal to (≧) 1, and y+z=2x+2.  
   
   
       15 . The formulation according to  claim 32  wherein the propellant is HFA 134a or HFA 227 or a mixture thereof.  
   
   
       16 . The formulation according to  claim 1  or  claim 2 , wherein the propellant is employed in an amount of greater than 90% by weight.  
   
   
       17 . The formulation according to  claim 1  or  claim 2 , wherein the ethanol is present in amounts of less than 2.5% by weight.  
   
   
       18 . The formulation according to  claim 1  or  claim 2  comprising a surfactant selected from the group consisting of oleic acid, lecithin, sorbitan trioleate, cetylpyridinium chloride, benzalkonium chloride, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, polyoxypropylene/polyoxyethylene block copolymers, polyoxypropylene/polyoxyethylene/ethylenediamine block copolymers, and ethoxylated castor oil.  
   
   
       19 . The formulation according to  claim 18  wherein the surfactant is present in an amount of 0.0001 to 1% by weight.  
   
   
       20 . A pharmaceutical aerosol formulation for use in a metered dose inhaler (MDI) comprising formoterol fumarate di-hydrate in suspension, a propellant and ethanol, wherein the moisture content of the formulation is in the range of from 50 ppm to 800 ppm.  
   
   
       21 . A vial containing the formulation according to  claim 1  or  claim 2 .  
   
   
       22 . The vial according to  claim 21  in the form of an aluminum, uncoated container.  
   
   
       23 . The vial according to  claim 21  adapted to be placed in a metered dose inhaler, and capable of delivering a dosage of formoterol fumarate di-hydrate of about 3 to 15 micro-grams.  
   
   
       24 . The vial according to  claim 21  adapted to be placed in a metered dose inhaler, and capable of delivering a dosage of a steroid of about 10 to 1000 micro-grams per puff.  
   
   
       25 . The vial according to  claim 24  adapted to be placed in a metered dose inhaler, and capable of delivering a dosage of fluticasone proprionate of about 50 to 500 micro-grams per puff.  
   
   
       26 . A package comprising the vial according to  claim 21  comprising a label containing a dosage claim, wherein the mean Delivered dose of the active substances is no more than +/−15% of the dosage stated on the label.  
   
   
       27 . A metered dose inhaler containing the vial according to  claim 21 .  
   
   
       28 . A method of producing a pharmaceutical aerosol formulation according to  claim 1  or  claim 2 , comprising drying the formoterol fumarate di-hydrate to a water content of 4.8 to 4.28%.  
   
   
       29 . The formulation according to  claim 13 , wherein the propellant is a fluorochlorocarbon selected from the group consisting of trichloro-monofluoromethane (F11), dichlorodifluoromethane (F12), monochlorotrifluoromethane (F13), dichloro-monofluoromethane (F21), monochlorodifluoromethane (F22), monochloromonofluoromethane (F31), 1,1,2-trichloro-1,2,2-trifluoroethane (F113), 1,2-dichloro-1,1,2,2-tetrafluoroethane (F114), 1-chloro-1,1,2,2,2-pentafluoroethane (F115), 2,2-dichloro-1,1,1-trifluoroethane (F123), 1,2-dichloro-1,1,2-trifluoroethane (F123a), 2-chloro-1,1,1,2-tetrafluoroethane (F124), 2-chloro-1,1,2,2-tetrafluoroethane (F124a), 1,2-dichloro-1,1-difluoroethane (F132b), 1-chloro-1,2,2-trifluoroethane (F 133), 2-chloro-1,1,1-trifluoroethane (F133a), 1,1-dichloro-1-fluoroethane (F141b) and 1-chloro-1,1-difluoroethane (F142b).  
   
   
       30 . The formulation according to  claim 13 , wherein the propellant is an alkane selected from the group consisting of propane, butane and isobutene.  
   
   
       31 . The formulation according to  claim 13 , wherein the propellant is octafluoropropane (F218).  
   
   
       32 . The formulation according to  claim 13 , wherein the propellant is a hydrofluoroalkanes selected from the group consisting of difluoromethane (HFA 32), pentafluoroethane (HFA 125), 1,1,2,2-tetrafluoroethane (HFA 134), 1,1,1,2-tetrafluoroethane (HFA 134a), 1,1,2-trifluoroethane (HFA 143), 1,1,1-trifluoroethane (HFA 143a), difluoroethane (HFA 152a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227).  
   
   
       33 . A metered dose inhaler containing the vial according to  claim 22.