Pharmaceutical manufacturing process

Abstract

The present invention provides a method for preparing a sterile suspension of a glucocorticosteroid. The glucocorticosteroids used in the invention are preferably antiinflammatory glucocorticosteroids. By making the last stage of product preparation be the sterilization process, the potential for contamination during manufacture and heat degradation of products is greatly reduced.

1 - 21 . (canceled) 
     
     
         22 . A composition comprising a sterile suspension of a glucocorticosteroid made by a process comprising the following steps: (i) heating a glucocorticosteroid suspension comprising a glucocorticosteroid, water and a surfactant in a mixing vessel to sterilize the glucocorticosteroid suspension, (ii) re-circulating the glucocorticosteroid suspension via a homogenizer before, during and/or after step (i), and subsequently (iii) mixing the glucocorticosteroid suspension with sterile water or a sterile excipient liquid comprising water and one or more pharmaceutically acceptable excipients. 
     
     
         23 . A composition as claimed in  claim 22 , wherein the method further comprises, prior to step (iii), the step of preparing the sterile water or sterile excipient liquid by passing water or an excipient liquid through a sterilizing grade filter. 
     
     
         24 . A composition as claimed in  claim 22 , wherein the sterile excipient liquid is used in step (iii) and the one or more pharmaceutically acceptable excipients comprises a surfactant. 
     
     
         25 . A composition as claimed in  claim 22 , wherein the sterile excipient liquid is used in step (iii) and the one or more pharmaceutically acceptable excipients comprises at least one of a buffer, a salt, a wetting agent, a stabilizing agent and an isotonic agent. 
     
     
         26 . A composition as claimed in  claim 22 , wherein the re-circulating in step (ii) occurs during the heating in step (i). 
     
     
         27 . A composition as claimed in  claim 22 , wherein the concentration of the glucocorticosteroid in the glucocorticosteroid suspension of step (i) is from about 15 to about 300 mg/ml. 
     
     
         28 . A composition as claimed in  claim 22 , wherein at least 50% of the glucocorticosteroid in the glucocorticosteroid suspension is in the form of a suspension during heating. 
     
     
         29 . A composition as claimed in  28 , wherein at least 60% of the glucocorticosteroid in the glucocorticosteroid suspension is in the form of a suspension during heating. 
     
     
         30 . A composition as claimed in  claim 22 , wherein the glucocorticosteroid is selected from the group consisting of at least one of beclomethasone, budesonide, ciclesonide, cortivazol, deflazacort, flumethasone, flunisolide, fluocinolone, fluticasone, mometasone, refleponide, tipredane and triamcinolone. 
     
     
         31 . A composition as claimed in  claim 29 , wherein the glucocorticosteroid is beclomethasone or budesonide. 
     
     
         32 . A composition as claimed in  claim 24 , wherein the concentration of the surfactant in the sterile excipient liquid is from about 0.2 to about 300 mg/ml. 
     
     
         33 . A composition as claimed in  claim 22 , wherein heating is carried out at a temperature of from about 101° C. to about 145° C. 
     
     
         34 . A composition as claimed in  claim 33 , wherein heating is carried out at a temperature of from about 122° C. to about 138° C. 
     
     
         35 . A composition as claimed in  claim 22 , wherein heating is carried out for about 2 to about 180 mins. 
     
     
         36 . A composition as claimed in  claim 35 , wherein heating is carried out for at least about 30 mins. 
     
     
         37 . A composition as claimed in  claim 22 , wherein the homogenizer is an in-line homogenizer or a high-pressure homogenizer. 
     
     
         38 . A composition as claimed in  claim 22 , wherein, in step (iii), the sterile excipient liquid is used and the glucocorticosteroid suspension is diluted with the sterile excipient liquid to a pharmaceutically suitable concentration. 
     
     
         39 . A composition as claimed in  claim 22 , wherein the sterile suspension of a glucocorticosteroid is packaged. 
     
     
         40 . A composition as claimed in  claim 39 , wherein the sterile suspension of a glucocorticosteroid is packaged by a blow-fill-seal (BFS) machine. 
     
     
         41 . A composition as claimed in  claim 22 , wherein the particle size of the glucocorticosteroid is such that the Dv100 is less than 20 μm, the Dv90 is less than 10 μm and the Dv50 is less than 5 μm. 
     
     
         42 . A composition as claimed in  claim 22 , wherein the sterile suspension is additionally comprised of a second active ingredient selected from the group consisting of albuterol, ipratropium bromide, cromolyn, formoterol, tiotropium, oxitropium and azelastine.