Inhaleable spray dried 4-helix bundle protein powders having minimized aggregation

Abstract

The present invention provides highly dispersible spray-dried powder compositions, and in particular, inhaleable dry powder compositions for aerosolized delivery to the lungs. The powders of the invention are produced by spray drying a 4 α-helix bundle protein under conditions which both (i) protect the protein from aggregation and (ii) provide particles suitable for inhalation (i.e., demonstrating superior aerosol performance).

1 - 52 . (canceled)  
     
     
         53 . An inhaleable pharmaceutical powder comprising spray-dried, inhaleable 4 alpha helix bundle particles, the particles comprising a 4 alpha helix bundle protein, the particles having an MMD of less than about 20 microns, the powder having superior aerosolizability and protein stability, wherein said powder is free from surfactant and characterized by (i) an emitted dose of at least about 65%, and (ii) a total protein aggregate content of less than 10%.  
     
     
         54 . The powder of  claim 53  wherein said 4 alpha helix bundle protein comprise a protein selected from the group consisting of an interferon, an interleukin and a colony stimulating factor.  
     
     
         55 . The powder of  claim 53 , wherein said 4 alpha helix bundle protein comprises a protein selected from the group consisting of: G-CSF, IFN-gamma, IFN-beta, GM-CSF, IL-2, IL-4, IL-5, and M-CSF.  
     
     
         56 . The powder of  claim 54  possessing a moisture content below about 6% by weight.  
     
     
         57 . The powder of  claim 54  wherein the particles have an MMAD of less than about 3.5 microns.  
     
     
         58 . The powder of  claim 54 , further comprising a stabilizing excipient, which when employed during spray-drying in combination with said 4 alpha helix bundle protein, is effective to maintain or lower the aggregate level of the powder in comparison to the corresponding neat formulation.  
     
     
         59 . The powder of  claim 58 , wherein said excipient is selected from the group consisting of sugars, amino acids and oligomers comprising 2-5 amino acids.  
     
     
         60 . The powder of  claim 59 , wherein said powder is rapid-acting.  
     
     
         61 . The powder of  claim 59 , wherein the excipient is sucrose or raffinose.  
     
     
         62 . The powder of  claim 59 , wherein the alpha helix protein is an interferon.  
     
     
         63 . The powder of  claim 59 , wherein the excipient is selected from the group consisting of asparagine, isoleucine, phenylalanine, tryptophan, tyrosine, leucine, norleucine and valine.  
     
     
         64 . The powder of  claim 63 , wherein the alpha helix protein is an interferon.  
     
     
         65 . The powder of  claim 59 , wherein said excipient is trileucine.  
     
     
         66 . The powder of  claim 65 , wherein the alpha helix protein is an interferon.  
     
     
         67 . The powder of  claim 58 , comprising less than about 30 percent by weight of said stabilizing excipient.  
     
     
         68 . The powder of  claim 58 , further characterized by a total aggregate content of less than about 10% after storage for one month at 40 degrees C.  
     
     
         69 . The powder of  claim 58 , comprising at least about 50% by weight 4 alpha helix bundle protein.  
     
     
         70 . A method for preparing an inhaleable 4 alpha helix bundle protein powder having superior aerosolizability and protein stability upon spray drying, said method comprising: 
 (a) dissolving a 4 alpha helix bundle protein in an aqueous solvent in the absence of surfactant to form a solution, and    (b) spray drying said solution under conditions effective to produce a powder characterized by (i) an emitted dose of at least about 65%, and (ii) a total protein aggregate content of less than 10%.    
     
     
         71 . The method of  claim 70 , wherein the alpha helix protein is an interferon.  
     
     
         72 . The method of  claim 70 , wherein the solution formed in step (a) has a solids content ranging from about 0.05 to about 5% by weight.  
     
     
         73 . The method of  claim 70 , wherein the solution formed in step (a) consists essentially of an interferon and a buffer.  
     
     
         74 . The method of  claim 70 , further comprising adding to the protein solution formed in step (a) a stabilizing excipient effective to maintain or lower the aggregate level of the powder in comparison to the neat formulation.  
     
     
         75 . The method of  claim 74 , wherein the stabilizing excipient is a sugar.  
     
     
         76 . The method of  claim 74 , wherein the stabilizing excipient is selected from the group consisting of amino acids and oligomers comprising 2-5 amino acids.  
     
     
         77 . The method of  claim 70 , wherein said conditions comprise spray drying said solution at atomization pressures in a range from about 30-80 psi.  
     
     
         78 . A spray-dried, inhaleable human powder having superior aerosolizability and protein stability, comprising an interferon, wherein said powder is free from surfactant and characterized by (i) an emitted dose of at least about 65%, and (ii) a total protein aggregate content of less than 10%.