Particles for inhalation having sustained release properties

Abstract

The invention generally relates to a method for pulmonary delivery of therapeutic, prophylactic and diagnostic agents to a patient wherein the agent is released in a sustained fashion, and to particles suitable for use in the method. In particular, the invention relates to a method for the pulmonary delivery of a therapeutic, prophylactic or diagnostic agent comprising administering to the respiratory tract of a patient in need of treatment, prophylaxis or diagnosis an effective amount of particles comprising a therapeutic, prophylactic or diagnostic agent or any combination thereof in association with a charged lipid, wherein the charged lipid has an overall net charge which is opposite to that of the agent upon association with the agent. Release of the agent from the administered particles occurs in a sustained fashion.

What is claimed is:  
     
         1 . A method for delivery via the pulmonary system comprising: 
 administering to the respiratory tract of a patient in need of treatment, prophylaxis or diagnosis an effective amount of particles comprising:    a bioactive agent in association with a charged lipid wherein the charged lipid has an overall net charge which is opposite to the overall net charge of the agent upon association and wherein release of the agent is sustained.    
     
     
         2 . The method of  claim 1 , wherein association of the agent and charged lipid comprises an ionic complexation.  
     
     
         3 . The method of  claim 2 , wherein association of the lipid and agent further comprises hydrogen bonding.  
     
     
         4 . The method of  claim 1 , wherein the charge ratio of lipid to bioactive agent is from about 0.25:1 to about 1:0.25.  
     
     
         5 . The method of  claim 4 , wherein the charge ratio of lipid to bioactive agent is from about 0.5:1 to about 1:0.5.  
     
     
         6 . The method of  claim 5  wherein the charge ratio of lipid to bioactive agent is about 1:1.  
     
     
         7 . The method of  claim 1  wherein the bioactive agent is a protein.  
     
     
         8 . The method of  claim 7  wherein the protein is insulin.  
     
     
         9 . The method of  claim 8 , wherein the sustained release is at least about 6 hours post administration.  
     
     
         10 . The method of  claim 1  wherein the bioactive agent is estrone sulfate.  
     
     
         11 . The method of  claim 1 , wherein the bioactive agent is albuterol sulfate.  
     
     
         12 . The method of  claim 1 , wherein the lipid possesses and overall net negative charge.  
     
     
         13 . The method of  claim 12 , wherein the lipid is a 1,2-diacyl-sn-glycero-3-[phospho-rac-( 1-glycerol)] and a 1,2-diacyl-sn-glycerol-3-phosphate.  
     
     
         14 . The method of  claim 13 , wherein the 1,2-diacyl-sn-glycero-3-[phospho-rac-(1-glycerol)] lipid is represented by Formula I:  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 1  and R 2  are independently an aliphatic group having from about 3 to about 24 carbons;  
 
     
     
         15 . The method of  claim 13  wherein the 1,2-diacyl-sn-glycero-3-[phospho-rac-(1-glycerol)] lipid is 1,2-distearoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (DSPG), 1,2-dimyristoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (DMPG), 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol)] (DPPG), 1,2-dilauroyl-sn -glycero-3-[phospho-rac-(1-glycerol)] (DLPG), 1,2-dioleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (DOPG) or any combination thereof.  
     
     
         16 . The method of  claim 13 , wherein the 1,2-diacyl-sn-glycerol-3-phosphate is represented by the Formula II  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 1  and R 2  are independently an aliphatic group having from about 3 to about 24 carbons;  
 
     
     
         17 . The method of  claim 13  wherein the 1,2-diacyl-sn-glycerol-3-phosphate lipid is 1,2-dimyristoyl-sn-glycero-3-phosphate (DMPA), 1,2-dipalmitoyl-sn-glycero-3-phosphate (DPPA), 1,2-dilauroyl-sn-glycero-3-phosphate (DLPA), 1,2-dioleoyl -sn-glycero-3-phosphate (DOPA), 1,2-distearoyl-sn-glycero-3-phosphate (DSPA) or any combination thereof.  
     
     
         18 . The method of  claim 1  wherein the particles have a tap density less than about 0.4 g/cm 3 .  
     
     
         19 . The method of  claim 18 , wherein the particles have a tap density less than about 0.1 g/cm 3 .  
     
     
         20 . The method of  claim 1 , wherein the particles have a median geometric diameter of from about 5 micrometers and about 30 micrometers.  
     
     
         21 . The method of  claim 1 , wherein the particles have an aerodynamic diameter of from about 1 to about 5 microns.  
     
     
         22 . The method of  claim 2   1 , wherein the particles have an aerodynamic diameter of from about 1 to about 3 microns.  
     
     
         23 . The method of  claim 22 , wherein the particles have an aerodynamic diameter of from about 3 to about 5 microns.  
     
     
         24 . The method of  claim 1 , wherein d elivery to the pulmonary system includes delivery to the deep lung.  
     
     
         25 . The method of  claim 1 , wherein delivery to the pulmonary system includes delivery to the central airways.  
     
     
         26 . The method of  claim 1 , wherein delivery to the pulmonary system includes delivery to the upper airways.  
     
     
         27 . The method of  claim 1 , wherein the particles further comprise a lipid having no overall net charge.  
     
     
         28 . The method of  claim 1  wherein the particles further comprise a carboxylic acid or salt thereof.  
     
     
         29 . The method of  claim 28 , wherein the carboxylic acid includes at least two carboxyl groups.  
     
     
         30 . The method of  claim 1 , wherein the particles further comprise a multivalent metal salt or ionic components thereof.  
     
     
         31 . The method of  claim 30 , wherein the multivalent salt is a salt of an alkaline earth metal.  
     
     
         32 . The method of  claim 1 , wherein the particles further comprise an amino acid.  
     
     
         33 . The method of  claim 32 , wherein the amino acid is hydrophobic.  
     
     
         34 . The method of  claim 33 , wherein the hydrophobic amino acid is leucine, isoleucine, alanine, valine, phenylalanine or any combination thereof.