Improved Medicinal Aerosol Formulations

Abstract

The present invention provides a medicinal aerosol suspension formulation for MDI administration, comprising: a) micronised pa-agonist; b) micronised corticosteroid; c) a siib-therapexrtic quantity of a moisture-scavenger excipient; and d) a HFA propellant; wherein (a), (b) and (c) and their respective relative amounts are selected such that they associate to form floccules having a density substantially the same as that of the HFA propellant.

1 . A medicinal aerosol suspension formulation for MDI administration, comprising:
 a) micronised β 2 -agonist;   b) micronised corticosteroid;   c) a sub-therapeutic quantity of a moisture-scavenger excipient; and   d) a HFA propellant;   wherein (a), (b) and (c) and their respective relative amounts are selected such that they associate to form floccules having a density substantially the same as that of the HFA propellant.   
     
     
         2 . A medicinal aerosol suspension formulation according to  claim 1 , wherein the average density of the floccules is substantially the same as the density of the propellant ±0.2 g/cm 3 ; preferably ±0.1 g/cm 3 ; and more preferably ±0.05 g/cm 3 . 
     
     
         3 . A medicinal aerosol suspension formulation according to  claim 1  or  claim 2 , wherein the HFA propellant is HFA 227. 
     
     
         4 . A medicinal aerosol suspension formulation according to any preceding claim, wherein the β 2 -agonist is formoterol fumarate or a pharmaceutically acceptable salt or derivative thereof. 
     
     
         5 . A medicinal aerosol suspension formulation according to any preceding claim, wherein the β 2 -agonist is present in an amount 0.003-0.04% by weight; preferably 0.04-0.03% by weight; and more preferably 0.005-0.02% by weight, based on the total weight of the formulation. 
     
     
         6 . A medicinal aerosol suspension formulation according to any preceding claim, wherein the corticosteroid is fluticasone propionate or a pharmaceutically acceptable salt or derivative thereof. 
     
     
         7 . A medicinal aerosol suspension formulation according to any preceding claim, wherein the corticosteroid is present in an amount 0.01-0.6% by weight; preferably between 0.02-0.5% by weight; and more preferably 0.03-0.4% by weight, based on the total weight of the formulation. 
     
     
         8 . A medicinal aerosol suspension formulation according to any preceding claim, wherein the moisture scavenger excipient is sodium cromolyn. 
     
     
         9 . A medicinal aerosol suspension formulation according to any preceding claim, wherein the moisture scavenger excipient is present in an amount of 0.01-0.1% by weight; preferably 0.016-0.09% by weight; and more preferably 0.02-0.08% by weight, more preferably 0.025-0.07% by weight, more preferably 0.03-0.05% by weight, more preferably 0.03-0.04% by weight, based on the total weight of the formulation. 
     
     
         10 . A medicinal aerosol suspension formulation c ding to any preceding claim, further comprising a wetting agent. 
     
     
         11 . A medicinal aerosol suspension formulation according to  claim 10 , wherein the wetting agent is a dehydrated alcohol. 
     
     
         12 . A medicinal aerosol suspension formulation according to  claim 11 , wherein the wetting agent is ethanol. 
     
     
         13 . A medicinal aerosol suspension formulation according to  claim 11  or  claim 12 , wherein in the alcohol is present in an amount of 0.01-3% by weight; preferably 0.05-2.5% by weight, and more preferably 1.0-2.0% by weight, based on the total weight of the formulation. 
     
     
         14 . A pharmaceutical composition comprising
 a) 0.01-0.6% by weight of micronised corticosteroid;   b) 0.003-0.04% by weight of micronised β 2 -agonist; and   c) 0.01-0.1% by weight of sodium cromolyn.   
     
     
         15 . A pharmaceutical composition according to  claim 14 , wherein the corticosteroid is micronised fluticasone propionate. 
     
     
         16 . A pharmaceutical composition according to  claim 14  or  claim 15 , wherein the β 2 -agonist is micronised formoterol fumarate dihydrate. 
     
     
         17 . A pharmaceutical composition according to any one of  claims 14  to  16 , further comprising a wetting agent. 
     
     
         18 . A pharmaceutical composition according to any one of  claims 14  to  17 , wherein the wetting agent is dehydrated alcohol, preferably ethanol, and preferably and is present in an amount of 0.01-3% by weight; preferably 0.05-2.5% by weight, and more preferably 1.0-2.0% by weight, based on the total weight of the formulation. 
     
     
         19 . A pharmaceutical suspension formulation comprising
 a) About 0.003-0.04% formoterol fumarate dihydrate;   b) About 0.01-0.6% fluticasone propionate;   c) About 0.01-0.1% suspension agent; and   d) About 00.1-3% dehydrated alcohol.   
     
     
         20 . A pharmaceutical suspension formulation according to  claim 19 , wherein the suspension agent is sodium cromolyn. 
     
     
         21 . A product containing formoterol fumarate dehydrate, fluticasone propionate and cromolyn sodium as a combined preparation for simultaneous, separate or sequential use in the treatment of inflammation and preferably for the treatment of asthma and allergic rhinitis. 
     
     
         22 . Use of sodium cromolyn in the preparation of a pharmaceutical suspension formulation in HFA propellant comprising formoterol fumarate dehydrate, fluticasone propionate microparticles for forming floccules of formoterol fumarate dehydrate, fluticasone propionate and sodium cromolyn having a density substantially the same as that of the HFA propellant. 
     
     
         23 . Use of 0.01 to 0.1% sodium cromolyn in the preparation of a pharmaceutical suspension formulation in HFA propellant comprising 0.003 to 0.004% formoterol fumarate dehydrate and 0.01 to 0.6% fluticasone propionate microparticles for forming floccules of formoterol fumarate dehydrate, fluticasone propionate and sodium cromolyn having a density substantially the same as that of the HFA propellant. 
     
     
         24 . Use of  claim 22  or  claim 23  wherein the average density of the floccules is substantially the same as the density of the propellant ±0.2 g/cm 3 ; preferably ±0.1 g/cm 3 ; and more preferably ±0.5 g/cm 3 . 
     
     
         25 . Use of any of  claims 22  to  24  wherein the pharmaceutical suspension formulation additionally comprises a wetting agent, preferably a dehydrated alcohol, preferably ethanol. 
     
     
         26 . A pharmaceutical composition comprising
 a) 0.0071 w/w formoterol fumarate dehydrate;   b) 0.0357 w/w, 0.0714 w/w, 0.1784 w/w or 0.3570 w/w fluticasone propionate;   c) 0.0343 w/w cromolyn sodium; and   d) the remainder comprising HFA 227 propellant.   
     
     
         27 . A pharmaceutical composition comprising
 a) 0.0142 w/w formoterol fumarate dehydrate;   b) 0.357 w/w fluticasone propionate;   c) 0.0343 w/w or 0.0686 w/w cromolyn sodium; and   d) the remainder comprising HFA 227 propellant.   
     
     
         28 . The composition of  claim 26  or  27 , further comprising 1.43 w/w ethanol, 
     
     
         29 . A method of increasing the stability of a medicinal aerosol suspension formulation of a micronised β 2 -agonist and a micronised corticosteroid in HFA propellant over a prolonged period of storage, comprising the addition of a sub-therapeutic amount of sodium cromoglycate, wherein the respective relative amounts of the micronised β 2 -agonist, micronised corticosteroid and sodium cromoglycate are selected such that they associate to form floccules having a density substantially the same as that of the HFA propellant. 
     
     
         30 . The method of  claim 29  wherein the prolonged storage is for 3, 6, 9, 12 or 18 months. 
     
     
         31 . The method of  claim 29  or  30  wherein the water content of the suspension formulation after prolonged storage is in the range of 500 ppm to 800 ppm, preferably 600 ppm to 700 ppm.