Aerosols containing annealed particulate salbutamol and tetrafluoroethane

Abstract

This invention relates to aerosol formulations of use for the administration of medicaments by inhalation. More particularly, the invention relates to a pharmaceutical aerosol formulation which comprises particulate salbutamol sulfate having a crystalline form in which the outer layer of the crystals is substantially non-amorphous; and 1,1,1,2-tetrafluoroethane. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as defined is also described.

1 . A drug product comprising: 
 a container containing a pharmaceutical aerosol formulation comprising annealed particulate salbutamol sulphate and 1,1,1,2-tetrafluoroethane; and,    a metering valve.    
     
     
         2 . The drug product of  claim 1  wherein the annealed particulate is substantially thermally inactive as measured by microcalorimetry at about 25° C. and between about 30% to about 90% relative humidity.  
     
     
         3 . The drug product of  claim 1  wherein the annealed particulate salbutamol sulphate is further micronised and includes a recrystallized outer surface layer.  
     
     
         4 . The drug product of  claim 1  wherein the annealed particulate salbutamol sulphate has a water content of less than about 0.4% by weight.  
     
     
         5 . The drug product of  claim 1  wherein the annealed particulate salbutamol sulphate has a water content of less than about 0.3% by weight.  
     
     
         6 . The drug product of  claim 1  wherein the annealed particulate salbutamol sulphate has a water content in the range of 0.01% to 1% by weight.  
     
     
         7 . The drug product of  claim 1  wherein the annealed particulate salbutamol sulphate has a water content in the range of 0.05% to 0.2% by weight.  
     
     
         8 . The drug product of  claim 1  wherein the pharmaceutical aerosol formulation consists essentially of the annealed particulate salbutamol sulphate and the 1,1,1,2-tetrafluoroethane.  
     
     
         9 . The drug product of  claim 1  wherein the container is an aluminum can having internal surfaces, and wherein the internal surfaces are coated with a coating comprising a fluorocarbon polymer.  
     
     
         10 . The drug product of  claim 9  wherein the fluorocarbon polymer is selected from the group consisting of polytetrafluoroethylene, fluorinated ethylene propylene, perfluoroalkoxyalkane, ethylene tetrafluoroethylene, vinyidienefluoride, chlorinated ethylene tetrafluoroethylene, copolymers thereof, and combinations thereof.  
     
     
         11 . The drug product of  claim 1  wherein the annealed particulate salbutamol sulphate is made by the acts, in any order, of: 
 subjecting particulate salbutamol sulphate to a temperature in the range of about 0° C. to about 100° C., and,  
 subjecting particulate salbutamol sulphate to a relative humidity in the range of about 20% to about 90%.  
 
     
     
         12 . The drug product of  claim 11  wherein the temperature is in the range of about 40° C. to about 100° C.  
     
     
         13 . The drug product of  claim 11  wherein the temperature is in the range of about 10° C. to about 50° C., and wherein the relative humidity is in the range of about 55% to about 65%.  
     
     
         14 . The drug product of  claim 11  wherein the temperature is in the range of about 20° C. to about 30° C.  
     
     
         15 . The drug product of  claim 11  wherein the temperature is about 25° C., and wherein the relative humidity is about 60%.  
     
     
         16 . The drug product of  claim 11  wherein the temperature is in the range of about 40° C. to about 100° C.  
     
     
         17 . The drug product of  claim 11  wherein the temperature is in the range of about 60° C. to about 100° C.  
     
     
         18 . The drug product of  claim 11  wherein the temperature is in the range of about 80° C. to about 100° C.  
     
     
         19 . The drug product of  claim 11  wherein the particulate salbutamol sulphate are subjected to the temperature and relative humidity acts for a duration sufficient to anneal.  
     
     
         20 . The drug product of  claim 19  wherein the duration is one or more weeks.  
     
     
         21 . The drug product of  claim 19  wherein the duration is in the range of 1 to 5 hours.  
     
     
         22 . The drug product of  claim 11  wherein the particulate salbutamol sulphate is contained in an open tray having a base comprising a plurality of apertures.  
     
     
         23 . The drug product of  claim 11  wherein the particulate salbutamol sulphate is contained in a means for permitting access of the humidity.  
     
     
         24 . The drug product of  claim 11  further including the act of micronising the particulate salbutamol sulphate producing annealed micronised salbutamol sulphate.  
     
     
         25 . The drug product of  claim 24  wherein the annealed micronised salbutamol sulphate has a particle size sufficient to permit inhalation of substantially all of the salbutamol sulphate into the lungs of a patient.  
     
     
         26 . The drug product of  claim 24  wherein the annealed micronised salbutamol sulphate has a particle size less than 100 microns.  
     
     
         27 . The drug product of  claim 24  wherein the annealed micronised salbutamol sulphate has a particle size less than 20 microns.  
     
     
         28 . The drug product of  claim 24  wherein the annealed micronised salbutamol sulphate has a particle size in the range of 1 to 10 microns.  
     
     
         29 . The drug product of  claim 24  wherein the annealed micronised salbutamol sulphate has a particle size in the range of 1 to 5 microns.  
     
     
         30 . The drug product of  claim 1  comprising 0.005 to 10% w/w annealed particulate salbutamol sulphate.  
     
     
         31 . The drug product of  claim 11  comprising 0.005 to 10% w/w annealed particulate salbutamol sulphate.  
     
     
         32 . The drug product of  claim 25  comprising 0.005 to 10% w/w annealed micronised salbutamol sulphate.  
     
     
         33 . The drug product of  claim 1  comprising 0.005 to 5% w/w annealed particulate salbutamol sulphate.  
     
     
         34 . The drug product of  claim 11  comprising 0.005 to 5% w/w annealed particulate salbutamol sulphate.  
     
     
         35 . The drug product of  claim 25  comprising 0.005 to 5% w/w annealed micronised salbutamol sulphate.  
     
     
         36 . The drug product of  claim 1  comprising 0.01 to 1% w/w annealed particulate salbutamol sulphate.  
     
     
         37 . The drug product of  claim 11  comprising 0.01 to 1% w/w annealed particulate salbutamol sulphate.  
     
     
         38 . The drug product of  claim 25  comprising 0.01 to 1% w/w annealed micronised salbutamol sulphate.  
     
     
         39 . The drug product of  claim 1  comprising 0.05 to 0.2% w/w annealed particulate salbutamol sulphate.  
     
     
         40 . The drug product of  claim 11  comprising 0.05 to 0.2% w/w annealed particulate salbutamol sulphate.  
     
     
         41 . The drug product of  claim 25  comprising 0.05 to 0.2% w/w annealed micronised salbutamol sulphate.  
     
     
         42 . The drug product of  claim 1  further comprising an adjuvant.  
     
     
         43 . The drug product of  claim 11  further comprising an adjuvant.  
     
     
         44 . The drug product of  claim 25  further comprising an adjuvant.  
     
     
         45 . The drug product of  claim 11  wherein the pharmaceutical aerosol formulation consists essentially of the annealed particulate salbutamol sulphate and the 1,1,1,2-tetrafluoroethane.  
     
     
         46 . The drug product of  claim 25  wherein the pharmaceutical aerosol formulation consists essentially of the annealed micronised salbutamol sulphate and the 1,1,1,2-tetrafluoroethane.  
     
     
         47 . The drug product of  claim 42  comprising 0.01% to 15% w/w of the adjuvant, wherein the adjuvant is an alcohol.  
     
     
         48 . The drug product of  claim 43  comprising 0.01% to 15% w/w of the adjuvant, wherein the adjuvant is an alcohol.  
     
     
         49 . The drug product of  claim 44  comprising 0.01% to 15% w/w of the adjuvant, wherein the adjuvant is an alcohol.  
     
     
         50 . The drug product of  claim 47  comprising 0.01% to 5% w/w of the adjuvant, wherein the adjuvant is ethanol.  
     
     
         51 . The drug product of  claim 48  comprising 0.01% to 5% w/w of the adjuvant, wherein the adjuvant is ethanol.  
     
     
         52 . The drug product of  claim 49  comprising 0.01% to 5% w/w of the adjuvant, wherein the adjuvant is ethanol.  
     
     
         53 . The drug product of  claim 42  wherein the adjuvant is a sugar selected from the group consisting of sucrose, dextrose and lactose.  
     
     
         54 . The drug product of  claim 43  wherein the adjuvant is a sugar selected from the group consisting of sucrose, dextrose and lactose.  
     
     
         55 . The drug product of  claim 44  wherein the adjuvant is a sugar selected from the group consisting of sucrose, dextrose and lactose.  
     
     
         56 . The drug product of  claim 53  wherein the adjuvant is lactose in an amount in the range of 0.0001% to 50% w/w.  
     
     
         57 . The drug product of  claim 54  wherein the adjuvant is lactose in an amount in the range of 0.0001% to 50% w/w.  
     
     
         58 . The drug product of  claim 55  wherein the adjuvant is lactose in an amount in the range of 0.0001% to 50% w/w.  
     
     
         59 . The drug product of  claim 53  wherein the adjuvant is lactose in an amount in the range of 0.001% to 20% w/w.  
     
     
         60 . The drug product of  claim 54  wherein the adjuvant is lactose in an amount in the range of 0.001% to 20% w/w.  
     
     
         61 . The drug product of  claim 55  wherein the adjuvant is lactose in an amount in the range of 0.001% to 20% w/w.  
     
     
         62 . The drug product of  claim 53  wherein the adjuvant is lactose in an amount in the range of 0.001% to 1% w/w.  
     
     
         63 . The drug product of  claim 54  wherein the adjuvant is lactose in an amount in the range of 0.001% to 1% w/w.  
     
     
         64 . The drug product of  claim 55  wherein the adjuvant is lactose in an amount in the range of 0.001% to 1% w/w.  
     
     
         65 . The drug product of  claim 1  further comprising a surfactant.  
     
     
         66 . The drug product of  claim 11  further comprising a surfactant.  
     
     
         67 . The drug product of  claim 25  further comprising a surfactant.  
     
     
         68 . The drug product of  claim 1  further comprising a surfactant in an amount up to 5% w/w.  
     
     
         69 . The drug product of  claim 11  further comprising a surfactant in an amount up to 5% w/w.  
     
     
         70 . The drug product of  claim 25  further comprising a surfactant in an amount up to 5% w/w.  
     
     
         71 . The drug product of  claim 1  substantially free of surfactant.  
     
     
         72 . The drug product of  claim 11  substantially free of surfactant.  
     
     
         73 . The drug product of  claim 25  substantially free of surfactant.  
     
     
         74 . The drug product of  claim 1  further comprising a second particulate medicament.  
     
     
         75 . The drug product of  claim 11  further comprising a second particulate medicament.  
     
     
         76 . The drug product of  claim 25  further comprising a second particulate medicament.  
     
     
         77 . The drug product of  claim 74  wherein the second particulate medicament is annealed.  
     
     
         78 . The drug product of  claim 75  wherein the second particulate medicament is annealed.  
     
     
         79 . The drug product of  claim 76  wherein the second particulate medicament is annealed.  
     
     
         80 . The drug product of  claim 74  wherein the second particulate medicament is micronised.  
     
     
         81 . The drug product of  claim 75  wherein the second particulate medicament is micronised.  
     
     
         82 . The drug product of  claim 76  wherein the second particulate medicament is micronised.  
     
     
         83 . The drug product of  claim 74  wherein the second particulate medicament is micronised and annealed.  
     
     
         84 . The drug product of  claim 75  wherein the second particulate medicament is micronised and annealed.  
     
     
         85 . The drug product of  claim 76  wherein the second particulate medicament is micronised and annealed.  
     
     
         86 . The drug product of  claim 74  wherein the second particulate medicament is selected from the group consisting of beclomethasone, fluticasone, cromoglycate, flunisolide, budesonide, tipredane, triamcinolone acetonide, and esters, solvates and salts thereof.  
     
     
         87 . The drug product of  claim 75  wherein the second particulate medicament is selected from the group consisting of beclomethasone, fluticasone, cromoglycate, flunisolide, budesonide, tipredane, triamcinolone acetonide, and esters, solvates and salts thereof.  
     
     
         88 . The drug product of  claim 76  wherein the second particulate medicament is selected from the group consisting of beclomethasone, fluticasone, cromoglycate, flunisolide, budesonide, tipredane, triamcinolone acetonide, and esters, solvates and salts thereof.  
     
     
         89 . The drug product of  claim 1  wherein the pharmaceutical aerosol formulation has a respirable fraction of 20% w/w or more of the annealed particulate salbutamol sulphate.  
     
     
         90 . The drug product of  claim 11  wherein the pharmaceutical aerosol formulation has a respirable fraction of 25% to 70% w/w of the annealed particulate salbutamol sulphate.  
     
     
         91 . The drug product of  claim 25  wherein the pharmaceutical aerosol formulation has a respirable fraction of 30% to 60% w/w of the annealed micronised salbutamol sulphate.  
     
     
         92 . The drug product of  claim 1  having a fixed unit dosage of annealed particulate salbutamol sulphate in the range of 10 to 5000 micrograms per actuation.  
     
     
         93 . The drug product of  claim 11  having a fixed unit dosage of annealed particulate salbutamol sulphate in the range of 10 to 5000 micrograms per actuation.  
     
     
         94 . The drug product of  claim 25  having a fixed unit dosage of annealed micronised salbutamol sulphate in the range of 10 to 5000 micrograms per actuation.  
     
     
         95 . The drug product of  claim 1  having a fixed unit dosage of annealed particulate salbutamol sulphate in the range of 100 to 1000 micrograms per actuation.  
     
     
         96 . The drug product of  claim 11  having a fixed unit dosage of annealed particulate salbutamol sulphate in the range of 100 to 1000 micrograms per actuation.  
     
     
         97 . The drug product of  claim 25  having a fixed unit dosage of annealed micronised salbutamol sulphate in the range of 100 to 1000 micrograms per actuation.  
     
     
         98 . A drug product comprising: 
 a container containing a pharmaceutical aerosol formulation comprising annealed particulate salbutamol sulphate and 1,1,1,2-tetrafluoroethane; and,    a means for metering the aerosol formulation.    
     
     
         99 . The drug product of  claim 1  wherein the annealed particulate salbutamol sulphate is made by the steps, in any order, of: 
 subjecting particulate salbutamol sulphate to a temperature in the range of about 0° C. to about 100° C., and,  
 subjecting particulate salbutamol sulphate to a relative humidity in the range of about 20% to about 90%.