Composition of matter

Abstract

The invention provides a process for the sterilization of a powdered form of a glucocorticosteroid, sterile glucocorticosteroids, sterile formulations containing glucocorticosteroids and use thereof in the treatment of an allergic and/or inflammatory condition of the nose or lungs.

1 .- 31 . (canceled)  
   
   
       32 . A method of manufacturing a sterile composition, the method comprising 
 (a) providing a powder composition comprising a glucocorticosteroid or an ester, acetal, or salt thereof, wherein the glucocorticosteroid contains an asymmetric acetal structure comprising 16α,17α-butylidenedioxy; and    (b) sterilizing the powder composition by a method comprising heat sterilization.    
   
   
       33 . The method of  claim 32 , wherein the heat sterilization comprises heating the powder composition to a temperature in the range of 100 to 130° C.  
   
   
       34 . The method of  claim 32 , wherein the heat sterilization comprises heating the powder composition to a temperature in the range of 100 to 120° C.  
   
   
       35 . The method of  claim 32 , wherein the heat sterilization comprises heating the powder composition to a temperature of about 110° C.  
   
   
       36 . The method of  claim 32 , wherein the glucocorticosteroid is an anti-inflammatory glucocorticosteroid.  
   
   
       37 . The method of  claim 32 , wherein the glucocorticosteroid or ester, acetal, or salt thereof is selected from the group consisting of budesonide, rofleponide, and rofleponide palmitate.  
   
   
       38 . The method of  claim 32 , wherein the heat sterilization is performed or no longer than 10 hours.  
   
   
       39 . The method of  claim 32 , wherein the heat sterilization is carried out in air.  
   
   
       40 . The method of  claim 63 , wherein the heat sterilization is carried out under an inert gas atmosphere.  
   
   
       41 . The method of  claim 32 , wherein the heat sterilization comprises a dry-heat treatment.  
   
   
       42 . The method of  claim 32 , wherein the glucocorticosteroid is budesonide.  
   
   
       43 . The method of  claim 32 , wherein the glucocorticosteroid is isomerically pure budesonide.  
   
   
       44 . The method of  claim 43 , wherein the budesonide is in the form of the (22R) diasteroisomer.  
   
   
       45 . The method of  claim 32 , wherein the powder composition contains less than about 1% (w/w) of water at a point just before the heat sterilization.  
   
   
       46 . The method of  claim 32 , wherein the powder composition consists of particles having a mass median diameter of less than 10 μm.  
   
   
       47 . The method of  claim 32 , wherein the powder composition consists of particles having a mass median diameter of less than 5 μm.  
   
   
       48 . The method of  claim 32 , wherein the number of heat resistant spores in the powder composition is reduced by more than log 6 by the heat sterilization.  
   
   
       49 . The method of  claim 32 , wherein the number of heat resistant spores in the powder composition is reduced by more than log 7 by the heat sterilization.  
   
   
       50 . The method of  claim 32 , wherein the heat sterilization comprises heating the powder composition for a time less than 90 minutes and at a temperature in the range of 100 to 130° C.  
   
   
       51 . A method of manufacturing a sterile composition, comprising 
 (a) providing a powder composition comprising particles of budesonide or an ester, acetal or salt thereof, wherein the particles have a mass median diameter of less than 10 μm; and    (b) dry-heating the powder composition at a temperature in the range of 100 to 130° C., thereby producing the sterile powder composition.    
   
   
       52 . The method of  claim 51 , wherein the temperature is in the range of from 100 to 120° C.  
   
   
       53 . The method of  claim 51 , wherein the temperature is in the range of about 110° C.  
   
   
       54 . The method of  claim 51 , wherein the powder composition is dry-heated for no longer than 10 hours.  
   
   
       55 . The method of  claim 51 , wherein the dry-heating is carried out in air.  
   
   
       56 . The method of  claim 51 , wherein the dry-heating is carried out under an inert gas atmosphere.  
   
   
       57 . The method of  claim 51 , wherein the budesonide is isomerically pure.  
   
   
       58 . The method of  claim 57 , wherein the budesonide is in the form of the (22R) diastereoisomer.  
   
   
       59 . The method of  claim 51 , wherein the powder composition contains less than about 1% (w/w) of water at a pint just before the dry-heating.  
   
   
       60 . The method of  claim 51 , wherein the particles of budesonide have a mass median diameter of less than 5 μm.  
   
   
       61 . The method of  claim 51 , wherein the number of heat resistant spores in the powder composition is reduced by more than log6 by the dry-heating.  
   
   
       62 . The method of  claim 51 , wherein the amount of heat resistant spores in the powder composition is reduced by more than log7 by the dry heating.  
   
   
       63 . A method of manufacturing a sterile composition, the method comprising 
 (a) manufacturing a powder composition comprising a glucocorticosteroid or an ester, acetal, or salt thereof, wherein the glucocorticosteroid contains an asymmetric acetal structure comprising 16α,17α-butylidenedioxy, and    (b) sterilizing the powder composition by a method comprising heat sterilization.    
   
   
       64 . The method of  claim 63 , further comprising combining the sterilized powder composition produced in step (b) with a sterile aqueous solution to produce a sterile aqueous suspension of the powder.  
   
   
       65 . The method of  claim 63 , wherein step (a) comprises micronizing the glucocorticosteroid or ester, acetal, or salt thereof to produce particles having a mass median diameter of less than 10 μm.  
   
   
       66 . The method of  claim 63 , wherein step (a) comprises micronizing the glucocorticosteroid or ester, acetal, or salt thereof to produce particles having a mass median diameter of less than 5 μm.  
   
   
       67 . The method of  claim 63 , wherein the heat sterilization comprises heating the powder composition to a temperature in the range of 100 to 130° C.  
   
   
       68 . The method of  claim 63 , wherein the heat sterilization comprises heating the powder composition to a temperature in the range of 100 to 120° C.  
   
   
       69 . The method of  claim 63 , wherein the heat sterilization comprises heating the powder composition to a temperature of about 110° C.  
   
   
       70 . The method of  claim 63 , wherein the glucocorticosteroid is an anti-inflammatory glucocorticosteroid.  
   
   
       71 . The method of  claim 63 , wherein the glucocorticosteroid or ester, acetal, or salt thereof is selected from the group consisting of budesonide, rofleponide, and rofleponide palmitate.  
   
   
       72 . The method of  claim 63 , wherein the heat sterilization is performed for no longer than 10 hours.  
   
   
       73 . The method of  claim 63 , wherein the heat sterilization is carried out in air.  
   
   
       74 . The method of  claim 63 , wherein the heat sterilization is carried out under an inert gas atmosphere.  
   
   
       75 . The method of  claim 63 , wherein the heat sterilization comprises a dry-heat treatment.  
   
   
       76 . The method of  claim 63 , wherein the glucocorticosteroid is budesonide.  
   
   
       77 . The method of  claim 63 , wherein the glucocorticosteroid is isomerically pure budesonide.  
   
   
       78 . The method of  claim 77 , wherein the budesonide is in the form of the (22R) diastereoisomer.  
   
   
       79 . The method of  claim 63 , wherein the powder composition contains less than about 1% (w/w) of water at a point just before the heat sterilization.  
   
   
       80 . The method of  claim 63 , wherein the number of heat resistant spores in the powder composition is reduced by more than log6 by the heat sterilization.  
   
   
       81 . The method of  claim 63 , wherein the number of heat resistant spores in the powder composition is reduced by more than log7 by the heat sterilization.