Pulmonary delivery particles comprising water insoluble or crystalline active agents

Abstract

A pulmonary delivery medicament comprises a plurality of particulates, the particulates comprising a structural matrix and a water insoluble and/or crystalline active agent. The particulates have a geometric diameter of 0.5 to 50 μm. The water insoluble active agent can be a fungicide, antibiotic, budesonide. A method of making the medicament comprises forming a liquid feedstock, and forming a feedstock suspension by suspending in the liquid feedstock, the active agent and an excipient capable of forming a structural matrix, such as a phospholipid. The feedstock suspension is spray dried to produce the particulates.

1 . A pulmonary delivery medicament comprising: 
 a plurality of particulates, the particulates having a perforated microstructure comprising a structural matrix and a water insoluble active agent, and the particulates having a geometric diameter of 0.5 to 50 μm.    
     
     
         2 . A medicament according to  claim 1  wherein the water insoluble active agent particle is crystalline.  
     
     
         3 . A medicament according to  claim 1  wherein the particulates further comprise an inorganic salt.  
     
     
         4 . A medicament according to  claim 1  wherein the particulates further comprise calcium.  
     
     
         5 . A medicament according to  claim 1  wherein the particulates comprise at least one of (i) a mass median diameter less than 10 μm, (ii) a mean aerodynamic diameter less than 5 μm, and (iii) a bulk density of less than about 0.5 g/cm 3 .  
     
     
         6 . A medicament according to  claim 1  wherein the structural matrix comprises a phospholipid structural matrix.  
     
     
         7 . A medicament according to  claim 6  wherein the phospholipid comprises dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, diarachidoylphosphatidylcholine dibehenoylphosphatidylcholine, diphosphatidyl glycerol, short-chain phosphatidylcholines, long-chain saturated phosphatidylethanolamines, long-chain saturated phosphatidylserines, long-chain saturated phosphatidylglycerols, or long-chain saturated phosphatidylinositols.  
     
     
         8 . A medicament according to  claim 1  wherein the particulates are formed by spray drying a liquid feedstock.  
     
     
         9 . A pulmonary delivery medicament comprising: 
 a plurality of particulates, the particulates having a perforated microstructure comprising a structural matrix and a crystalline active agent, and the particulates having a geometric diameter of 0.5 to 50 μm.    
     
     
         10 . A medicament according to  claim 9  wherein the crystalline active agent is water insoluble.  
     
     
         11 . A medicament according to  claim 9  wherein the particulates comprise an inorganic salt.  
     
     
         12 . A medicament according to  claim 9  wherein the particulates comprise calcium.  
     
     
         13 . A medicament according to  claim 9  wherein the particulates comprise at least one of (i) a mass median diameter less than 10 μm, (ii) a mean aerodynamic diameter less than 5 μm, and (iii) a bulk density of less than about 0.5 g/cm 3 .  
     
     
         14 . A medicament according to  claim 9  wherein the structural matrix comprises a phospholipid structural matrix.  
     
     
         15 . A medicament according to  claim 14  wherein the phospholipid comprises dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, diarachidoylphosphatidylcholine dibehenoylphosphatidylcholine, diphosphatidyl glycerol, short-chain phosphatidylcholines, long-chain saturated phosphatidylethanolamines, long-chain saturated phosphatidylserines, long-chain saturated phosphatidylglycerols, or long-chain saturated phosphatidylinositols.  
     
     
         16 . A pulmonary delivery medicament comprising: 
 a plurality of particulates, the particulates having a perforated microstructure comprising a structural matrix and a water insoluble active agent comprising a fungicide, and the particulates having a geometric diameter of 0.5 to 50 μm.    
     
     
         17 . A pulmonary delivery medicament comprising: 
 a plurality of particulates, the particulates having a perforated microstructure comprising a structural matrix and a water insoluble active agent comprising an antibiotic, and the particulates having a geometric diameter of 0.5 to 50 μm.    
     
     
         18 . A pulmonary delivery medicament comprising: 
 a plurality of particulates, the particulates having a perforated microstructure comprising a structural matrix and a water insoluble active agent comprising a budesonide, and the particulates having a geometric diameter of 0.5 to 50 μm.    
     
     
         19 . A method of making a medicament for pulmonary delivery, the method comprising: 
 (a) forming a liquid feedstock;    (b) forming a feedstock suspension by suspending in the liquid feedstock, a water insoluble active agent and an excipient capable of forming a structural matrix; and    (b) spray drying the feedstock suspension to produce a plurality of particulates, the particulates having a perforated microstructure comprising a structural matrix and water insoluble active agent, and the particulates having a geometric diameter of 0.5 to 50 μm.    
     
     
         20 . A method according to  claim 19  wherein the water insoluble active agent is crystalline.  
     
     
         21 . A method according to  claim 19  wherein the liquid feedstock comprises water.  
     
     
         22 . A method according to  claim 19  further comprising adding an inorganic salt to the liquid feedstock.  
     
     
         23 . A method according to  claim 19  wherein (a) comprises forming a liquid feedstock absent a blowing agent.  
     
     
         24 . A method according to  claim 19  wherein the excipient comprises at least one phospholipid, and wherein (b) comprises spray drying the feedstock suspension to produce particulates comprising a phospholipid structural matrix.  
     
     
         25 . A method according to  claim 24  wherein the phospholipid comprises dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, diarachidoylphosphatidylcholine dibehenoylphosphatidylcholine, diphosphatidyl glycerol, short-chain phosphatidylcholines, long-chain saturated phosphatidylethanolamines, long-chain saturated phosphatidylserines, long-chain saturated phosphatidylglycerols, or long-chain saturated phosphatidylinositols.  
     
     
         26 . A method for making a medicament for pulmonary delivery, the method comprising: 
 (a) providing a feedstock suspension comprising a crystalline active agent suspended in a liquid;    (b) atomizing the feedstock suspension to produce dispersed droplets;    (c) spray drying the feedstock suspension to produce a plurality of particulates, the particulates having a perforated microstructure comprising a structural matrix and the crystalline active agent, the particulates having a geometric diameter of 0.5 to 50 μm.    
     
     
         27 . A method according to  claim 26  wherein the active agent is water insoluble.  
     
     
         28 . A method according to  claim 26  wherein the liquid comprises water.  
     
     
         29 . A method according to  claim 26  wherein (a) comprises adding an inorganic salt to the feedstock suspension.  
     
     
         30 . A method according to  claim 29  wherein the inorganic salt comprises calcium.