Mass Production and Size Control of Nanoparticles Through Controlled Microvortices

Abstract

Methods for making particles, such as nanoparticles, devices useful in the methods, and particles made by the method are described herein. The methods involves the use of a microfluidic device, such that upon mixing solutions of the materials to form the particles (or a solution of the material or materials to form the particles and a non-solvent for the material or materials), at least two symmetrical microvortices are formed simultaneously. The method can be used to prepare polymeric or non-polymeric particles and hybrid particles, such as lipid-polymer hybrid particles, as well as such particles containing one or more agents associated with the particles.

1 . A method of making nanoparticles comprising mixing in a microfluidic device a solution of one or more materials with a non-solvent for the one or more materials to form a three-dimensional pattern comprising at least two symmetrical microvortices and focusing the pattern downstream to form the nanoparticles. 
     
     
         2 . The method of  claim 1 , wherein the particles are polymeric nanoparticles formed by mixing a solution comprising a polymer with a non-solvent for the polymer. 
     
     
         3 . The method of  claim 1 , wherein the particles are lipid-polymer hybrid nanoparticles forming mixing a solution comprising a polymer with a solution comprising one or more lipids. 
     
     
         4 . The method of  claim 2 , wherein the solvent in the polymer solution is an organic solvent. 
     
     
         5 . The method of  claim 1 , wherein the non-solvent for the material or polymer is water or an aqueous solvent. 
     
     
         6 . The method of  claim 3 , wherein the solvent in the lipid solution is water or an aqueous solvent. 
     
     
         7 . The method of  claim 2 , wherein the polymer is a naturally occurring polymer. 
     
     
         8 . The method of  claim 2 , wherein the polymer is a synthetic polymer. 
     
     
         9 . The method of  claim 7 , wherein the polymer is biocompatible. 
     
     
         10 . The method of  claim 2 , wherein the polymer is biodegradable. 
     
     
         11 . The method of  claim 2 , wherein the one or more polymers are selected from the group consisting of polyesters, polyanhydrides, polyalkylene oxides, and copolymers and blends thereof. 
     
     
         12 . The method of  claim 11 , wherein the polymer is polylactide-co-glycolide. 
     
     
         13 . The method of  claim 7 , wherein the polymer comprises a protein. 
     
     
         14 . The method of  claim 1 , wherein the one or more materials are lipids. 
     
     
         15 . The method of  claim 14 , wherein the one or more materials are phospholipids. 
     
     
         16 . The method of  claim 14 , wherein the lipid or phospholipid is dissolved in a lower alcohol (e.g., methanol or ethanol) or an organic solvent (e.g., chloroform). 
     
     
         17 . The method of  claim 3 , wherein the one or more lipids are selected from the group consisting of lecithin, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)], dimyristoylphosphatidylcholine (DMPC), 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC), 1-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC), and combinations thereof. 
     
     
         18 . The method of  claim 1 , wherein the solution of the material or polymer, the lipid solution, or combinations thereof further contain a bioactive agent. 
     
     
         19 . The method of  claim 18 , wherein the bioactive agent is a diagnostic, prophylactic, therapeutic agent, nutriceutical agent, or combinations thereof. 
     
     
         20 . The method of  claim 14 , wherein the active agent is apoA-I. 
     
     
         21 . The method of  claim 20 , wherein the nanoparticles further comprise an additional therapeutic or diagnostic agent. 
     
     
         22 . The method of  claim 21 , wherein the additional agent is a cholesterol-lowering agent, such as a statin. 
     
     
         23 . The method of  claim 1 , wherein the nanoparticles are formed at a rate of greater than 0.1 grams of nanoparticles per hour of fluid flow. 
     
     
         24 . The method of  claim 23 , wherein the nanoparticles are formed at a rate of greater than 1.0 grams of nanoparticles per hour of fluid flow. 
     
     
         25 . The method of  claim 24 , wherein the nanoparticles are formed at a rate of greater than 2.0 grams of nanoparticles per hour of fluid flow. 
     
     
         26 . The method of  claim 25 , wherein the nanoparticles are formed at a rate of greater about 3.0 grams of nanoparticles per hour of fluid flow. 
     
     
         27 . The method of  claim 1 , wherein the nanoparticles have an average particle size of between about 5 nm and about 200 nm. 
     
     
         28 . The method of  claim 1 , wherein the device comprises three inlets and wherein the device is configured such that the ratio of the fluid flow rate in the central fluid inlet channel to the combined fluid flow rate in the two outer fluid inlet channels is between about 1:10 and about 1:30. 
     
     
         29 . The method of  claim 28 , wherein the device is configured such that the ratio of the fluid flow rate in the central fluid inlet channel to the combined fluid flow rate in the two outer fluid inlet channels is between about 1:10 and about 1:20. 
     
     
         30 . The method of  claim 1 , wherein the microvortices are generated at a Reynolds number regime greater than about 30. 
     
     
         31 . The method of  claim 30 , wherein the Reynolds number is from about 30 to about 150. 
     
     
         32 . The method of  claim 31 , wherein the Reynolds number is from about 30 to about 100. 
     
     
         33 . A multi-inlet microfluidic device comprising three fluid inlet channels which converge in a mixing channel, the devices comprising one or more of the following features:
 (a) the height of the fluid inlet channels is greater than the width of the fluid inlet channels,   (b) the distance between adjacent fluid inlet channels is greater than the width of the fluid inlet channels,   (c) the width of the mixing channel is at least six times the width of the fluid inlet channels,   (d) the height of the mixing channel is more than 1.5 times the width of the fluid inlet channels, and   (e) the length of the mixing channel is at least two times the width of the mixing channel.   
     
     
         34 . The device of  claim 33 , wherein the width of the fluid inlet channels is between about 10 and about 500 microns, preferably about 200 microns. 
     
     
         35 . The device of  claim 33 , wherein the height of the fluid inlet channels is between about 20 and about 1000 microns, preferably about 400 microns. 
     
     
         36 . The device of  claim 33 , wherein the length of the inlet channels is about 10 mm to about 20 mm, preferably about 10 mm. 
     
     
         37 . The device of  claim 33 , wherein the width of the mixing channel is greater than 100 microns, preferably greater than 1000 microns, more preferably greater than or equal to about 2000 microns. 
     
     
         38 . The device of  claim 33 , wherein the length of the mixing channel is greater than about 10 millimeters, preferably greater than 15 millimeters, more preferably greater than or equal to about 20 millimeters. 
     
     
         39 . A population of particles made by the method of  claim 1 . 
     
     
         40 . The population of  claim 39 , wherein the particles have an average largest dimension of about 5 nm to about 200 nm. 
     
     
         41 . The population of  claim 40 , wherein the polydispersity is about 0.1 or less.