Stable spray-dried protein formulations

Abstract

Spray-dried particles having improved protein stability are produced by spray-drying a mixture including a protein, a phospholipid and an organic-aqueous co-solvent. Spray-dried particles which include at least 1 weight % phospholipid, having a tap density of less than 0.4 g/cm 3 can be prepared. The particles can be delivered to the pulmonary system of a patient.

1 . A method for producing spray-dried particles having improved stability of a protein comprising: 
 (a) combining a protein, buffer, a phospholipid and a co-solvent, said co-solvent including an aqueous solvent and an organic solvent, to form a mixture; and    (b) spray-drying said mixture to produce spray-dried particles having improved stability of the protein;    wherein the particles consist essentially of protein, buffer and the phospholipid and the protein is insulin.    
     
     
         2 . The method of  claim 1 , wherein the spray-dried particles consist of insulin, buffer and the phospholipid.  
     
     
         3 . The method of  claim 1 , wherein the phospholipid is selected from the group consisting of phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols and combinations thereof.  
     
     
         4 . The method of  claim 1 , wherein the phospholipid is dipalmitoylphosphatidylcholine.  
     
     
         5 . The method of  claim 1 , wherein the protein is present in the spray-dried particles in an amount ranging from about 1 to about 90 weight %.  
     
     
         6 . The method of  claim 1 , wherein the phospholipid is present in an amount of at least 10 weight %.  
     
     
         7 . The method of  claim 1 , wherein the spray-dried particles retain at least about 70% protein integrity when stored at about 25° C. and about 60% relative humidity conditions for six weeks.  
     
     
         8 . The method of  claim 1 , wherein the spray-dried particles retain at least about 50% protein integrity when stored at about 40° C. and about 75% relative humidity conditions for six weeks.  
     
     
         9 . The method of  claim 1 , wherein the protein and phospholipid concentration in said mixture is at least 0.1 weight/volume %.  
     
     
         10 . The method of  claim 1 , wherein the co-solvent includes an alcohol.  
     
     
         11 . The method of  claim 1 , wherein the organic solvent is present in the co-solvent in a concentration of at least 50 volume %.  
     
     
         12 . The method of  claim 1 , wherein the spray-dried particles have a tap density less than about 0.4 g/cm 3 .  
     
     
         13 . The method of  claim 12  wherein the spray-dried particles have a tap density less than about 0.1 g/cm 3 .  
     
     
         14 . The method of  claim 12 , wherein the spray-dried particles have a tap density less than about 0.05 g/cm 3 .  
     
     
         15 . The method of  claim 1 , wherein the spray-dried particles have a median geometric diameter of between about 5 microns and about 30 microns.  
     
     
         16 . The method of  claim 1 , wherein the spray-dried particles have an aerodynamic diameter of between about 1 micron and about 5 micron.  
     
     
         17 . The particles produced by the method of  claim 1 .  
     
     
         18 . A method comprising administering to the respiratory tract of a patient in need of treatment, prophylaxis or diagnosis an effective amount of the spray-dried particles produced by the method of  claim 1.