# US 10,864,162 B2 · Mass production and size control of nanoparticles through controlled microvortices > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,864,162 B2 - Document ID: US10864162B2 - Status: Granted - Kind: B2 - Application number: 15/617,557 - Filed: 2017-06-08 - Published: 2017-11-23 - Granted: 2020-12-15 - Earliest claimed: 2012-06-19 - Assignees: Massachusetts Institute of Technology; The Brigham and Women's Hospital, Inc.; Icahn School of Medicine at Mount Sinai - Applicants: Massachusetts Institute of Technology; The Brigham and Women's Hospital, Inc.; Icahn School of Medicine at Mount Sinai; New York University - Inventors: YongTae Kim; Zahi Fayad; Willem J. Mulder; Edward Fisher; Francois Fay; Omid C. Farokhzad; Robert Langer - Web page: https://patentgrep.com/patent/US10864162B2 ## CPC - A61K 9/146: {with organic macromolecular compounds} - A61K 9/145: {with organic compounds} - A61K 9/5153: {Polyesters, e.g. poly(lactide-co-glycolide)} - A61K 9/5176: {Compounds of unknown constitution, e.g. material from plants or animals (oils, fats, waxes, shellac A61K9/5123)} - A61K 9/5192: {Processes} - Y10T 428/2982: Particulate matter [e.g., sphere, flake, etc.] - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION ## 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 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. ## Claims ### Claim 1 A method of making nanoparticles comprising mixing in a microfluidic device comprising a central fluid inlet channel and two outer fluid inlet channels, wherein the channels converge in a mixing channel prior to the outlet, a solution of one or more materials selected from polymers and lipids 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, wherein 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 in a ratio of between about 1:10 and about 1:30, and wherein the symmetrical microvortices, generated at a Reynolds number of greater than about 30, produce an effective amount of convective mixing of the solution of one or more materials and the non-solvent to produce a population of the nanoparticles having a homogeneous size distribution. ### Claim 2 (depends on 1) The method of claim 1, wherein the nanoparticles are polymeric nanoparticles. ### Claim 3 (depends on 1) The method of claim 1, wherein the nanoparticles are lipid-polymer hybrid nanoparticles formed by mixing a solution comprising polymer with the non-solvent comprising one or more lipids. ### Claim 4 (depends on 1) The method of claim 1, wherein the non-solvent is an organic solvent. ### Claim 5 (depends on 1) The method of claim 1, wherein the non-solvent is water or an aqueous solvent. ### Claim 6 (depends on 3) The method of claim 3, wherein the non-solvent is water or an aqueous solvent. ### Claim 7 (depends on 1) The method of claim 1, wherein the polymer is a naturally occurring polymer. ### Claim 8 (depends on 1) The method of claim 1, wherein the polymer is a synthetic polymer. ### Claim 9 (depends on 7) The method of claim 7, wherein the polymer is biocompatible. ### Claim 10 (depends on 1) The method of claim 1, wherein the polymer is biodegradable. ### Claim 11 (depends on 1) The method of claim 1, wherein the polymer is selected from the group consisting of polyesters, polyanhydrides, polyalkylene oxides, and copolymers and blends thereof. ### Claim 12 (depends on 11) The method of claim 11, wherein the polymer is polylactide-co-glycolide. ### Claim 13 (depends on 7) The method of claim 7, wherein the polymer comprises a protein. ### Claim 14 (depends on 1) The method of claim 1, wherein the one or more materials are lipids. ### Claim 15 (depends on 1) The method of claim 1, wherein the lipid is a phospholipid. ### Claim 16 (depends on 14) The method of claim 14, wherein the lipid is dissolved in a lower alcohol or an organic solvent. ### Claim 17 (depends on 3) 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. ### Claim 18 (depends on 1) The method of claim 1, wherein the solution further contains a bioactive agent. ### Claim 19 (depends on 18) The method of claim 18, wherein the bioactive agent is a diagnostic, prophylactic, therapeutic agent, nutriceutical agent, or combinations thereof. ### Claim 20 (depends on 18) The method of claim 18, wherein the bioactive agent is apolipoprotein A-I. ### Claim 21 (depends on 1) The method of claim 1, wherein the nanoparticles further comprise an additional therapeutic or diagnostic agent. ### Claim 22 (depends on 21) The method of claim 21, wherein the additional agent is a cholesterol-lowering agent. ### Claim 23 (depends on 1) 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. ### Claim 24 (depends on 23) 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. ### Claim 25 (depends on 24) 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. ### Claim 26 (depends on 25) 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. ### Claim 27 (depends on 1) The method of claim 1, wherein the nanoparticles have an average particle size of between about 5 nm and about 200 nm. ### Claim 28 (depends on 1) The method of claim 1, wherein the fluid flow rate in the central fluid inlet channel to the relative combined fluid flow rate in the two outer fluid inlet channels is between about 1:10 and about 1:20. ### Claim 29 (depends on 1) The method of claim 1, wherein the symmetrical microvortices are generated at a Reynolds number of between about 30 to 150. ### Claim 30 (depends on 29) The method of claim 29, wherein the Reynolds number is from about 30 to about 100. ### Claim 31 (depends on 1) The method of claim 1, wherein the width of the central fluid inlet channel and the two outer fluid inlet channels is between about 10 and about 500 microns. ### Claim 32 (depends on 1) The method of claim 1, wherein the height of the central fluid inlet channel and the two outer fluid inlet channels is between about 20 and about 1000 microns. ### Claim 33 (depends on 1) The method of claim 1, wherein the length of the central fluid inlet channel and the two outer fluid inlet channels is about 10 mm to about 20 mm. ### Claim 34 (depends on 1) The method of claim 1, wherein the width of the mixing channel is greater than 100 microns. ### Claim 35 (depends on 1) The method of claim 1, wherein the length of the mixing channel is greater than about 10 millimeters. ### Claim 36 (depends on 1) The method of claim 1, wherein the population of the nanoparticles have a polydispersity of about 0.1 or less. ### Claim 37 (depends on 1) The method of claim 1, wherein the nanoparticles are lipid nanoparticles.