Micronized freeze-dried particles

Abstract

A process is provided for making dry, micronized particles of an agent, such as a drug. The method includes (a) dissolving a macromolecular material, preferably a polymer, in an effective amount of a solvent, to form a solution; (b) dissolving or dispersing the agent in the solution to form a mixture; (c) freezing the mixture; and (d) drying by vacuum the mixture to form solid particles of the agent dispersed in solid macromolecular material. The micronization in this process occurs directly in a macromolecular matrix and hardening of the particles of agent by solvent removal takes place by lyophilization of the bulk matrix, which stabilizes the drug particles during hardening and prevents coalesence, thereby resulting in smaller final drug particles. The method is particularly preferred for protein agents. The process can be used in conjunction with a standard microencapsulation technique, typically following separation of the agent from the macromolecular matrix. The process yields microparticles having a homogenous size distribution, preferably less than 2 μm, and more preferably less than 1 μm, in size. The microparticles have well defined, predictable properties, which is particularly critical in drug delivery applications.

We claim:  
     
         1 . A method for making dry, micronized particles of an agent, comprising: 
 (a) dissolving a macromolecular material in an effective amount of a solvent, to form a solution;    (b) dissolving or dispersing the agent in the solution to form a mixture;    (c) freezing the mixture; and    (d) drying by vacuum the mixture to form solid particles of the agent dispersed in solid macromolecular material.    
     
     
         2 . The method of  claim 1  further comprising separating the solid particles of agent from the solid macromolecular material.  
     
     
         3 . The method of  claim 2  further comprising encapsulating the solid particles of agent in an encapsulating material.  
     
     
         4 . The method of  claim 1  wherein greater than 90% solid particles are less than 0.2 μm in size.  
     
     
         5 . The method of  claim 4  wherein greater than 90% solid particles less than 1 μm in size.  
     
     
         6 . The method of  claim 1  wherein greater than 90% of the solid particles are between 10 nm and 1 μm.  
     
     
         7 . The method of  claim 1  wherein the agent is a bioactive agent.  
     
     
         8 . The method of  claim 7  wherein the bioactive agent is a protein.  
     
     
         9 . The method of  claim 8  wherein the protein is a growth hormone.  
     
     
         10 . The method of  claim 8  wherein the protein is an osteoprotegrenin.  
     
     
         11 . The method of  claim 7  wherein the agent is selected from the group consisting of peptides, antibiotics, nucleotide molecules, and synthetic drugs.  
     
     
         12 . The method of  claim 1  wherein the macromolecular material is a polymer.  
     
     
         13 . The method of  claim 12  wherein the polymer is selected from the group consisting of polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, polyurethanes, poly(butic acid), poly(valeric acid), poly(caprolactone), poly(hydroxybutyrate), poly(lactide-co-glycolide), poly(lactide-co-caprolactone), and blends and copolymers thereof.  
     
     
         14 . The method of  claim 1  wherein the mixture of step (b) is an emulsion.  
     
     
         15 . The method of  claim 1  wherein step (d) utilizes lyophilization.  
     
     
         16 . The method of  claim 3  wherein the encapsulation is conducting using a process selected from the group consisting of interfacial polycondensation, spray drying, hot melt microencapsulation, and phase separation techniques.  
     
     
         17 . The method of  claim 12  wherein the phase separation technique is selected from the group consisting of solvent extraction, solvent evaporation, and phase inversion.  
     
     
         18 . The method of  claim 17  wherein the mixture has a continuous phase containing the solvent and wherein the phase inversion technique comprises: 
 introducing the mixture into a nonsolvent, wherein the volume ratio of solvent:nonsolvent is at least 1:40, to cause the spontaneous formation of a microencapsulated product, wherein the solvent and the nonsolvent are miscible.  
 
     
     
         19 . The method of  claim 18  wherein 0 less than δ solvent-δ nonsolvent less than 6.  
     
     
         20 . The method of  claim 18  wherein the volume ratio of solvent:nonsolvent is between 1:50 and 1:200.  
     
     
         21 . The method of  claim 18  wherein the macromolecular material is dissolved in the solvent at a concentration of less than 10% weight per volume and wherein the mixture has a viscosity of less than 3.5 cP.  
     
     
         22 . The method of  claim 20  wherein the concentration of the macromolecular material in the solvent is between 0.5 and 5% weight per volume.  
     
     
         23 . The method of  claim 8  wherein freezing of the mixture is performed sufficiently rapidly following addition of the agent to the solution such that denaturing of the protein is substantially avoided.  
     
     
         24 . The method of  claim 2  wherein the particles of agent are separated from the solid macromolecular material using a method comprising 
 dissolving the macromolecular material in an effective amount of a solvent for the macromolecular material, wherein the solvent is a nonsolvent for the agent.  
 
     
     
         25 . The method of  claim 3  wherein the encapsulating material is a biocompatible polymer.  
     
     
         26 . The method of  claim 25  wherein the biocompatible polymer is selected from polyesters, polyanhydrides, polystyrenes, poly(ortho)esters, copolymers thereof, and blends thereof.  
     
     
         27 . A polymeric or macromolecular composition comprising particles of a bioactive agent, wherein more than 90% of the bioactive agent particles are less than 2 μm in size.  
     
     
         28 . The composition of  claim 27  wherein more than 90% of the particles are less than 1 μm in size.  
     
     
         29 . The composition of  claim 27  wherein particles are dispersed in a solid macromolecular material.  
     
     
         30 . The composition of  claim 29  wherein the material is a polymer.  
     
     
         31 . The composition of  claim 27  made by a process comprising: 
 (a) dissolving a macromolecular material in an effective amount of a solvent, to form a solution;  
 (b) dissolving or dispersing the bioactive agent in the solution to form a mixture;  
 (b) freezing the mixture; and  
 (c) drying by vacuum the mixture to form dry, solid particles of the agent dispersed in solid macromolecular material.  
 
     
     
         32 . The composition of  claim 27  in a pharmaceutically acceptable carrier.  
     
     
         33 . A method enhancing delivery a bioactive agent to a patient in need thereof comprising administering the bioactive agent as particles, wherein more than 90% of the particles are less than 2 μm in size.