Continuous flow microfluidic system

Abstract

The present disclosure is directed towards improved systems and methods for large-scale production of nanoparticles used for delivery of therapeutic material. The apparatus can be used to manufacture a wide array of nanoparticles containing therapeutic material including, but not limited to, lipid nanoparticles and polymer nanoparticles. In certain embodiments, continuous flow operation and parallelization of microfluidic mixers contribute to increased nanoparticle production volume.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: 
     
         1 . A system for continuous flow operation of a microfluidic chip, the system comprising:
 (1) a microfluidic chip, comprising:
 (a) a first inlet configured to receive a first solution; 
 (b) a second inlet configured to receive a second solution; and 
 (c) a first mixer, comprising:
 (i) a first inlet microchannel configured to receive the first solution from the first inlet; 
 (ii) a second inlet microchannel configured to receive the second solution from the second inlet; and 
 (iii) a mixing microchannel configured to mix the first solution and the second solution to provide a nanoparticle solution at a mixer outlet; and 
 
 (d) a chip outlet in fluid communication with the mixer outlet through a nanoparticle solution microchannel; 
   (2) a first continuous flow fluid driver configured to continuously drive the first solution from a first solution reservoir into the first inlet of the microfluidic chip;   (3) a second continuous flow fluid driver configured to continuously drive the second solution from a second solution reservoir into the second inlet of the microfluidic chip; and   (4) a system outlet in fluid communication with the chip outlet, wherein the system outlet is configured to output the nanoparticle solution.   
     
     
         2 . The system of  claim 1 , wherein the first solution comprises an active pharmaceutical ingredient. 
     
     
         3 . The system of  claim 1 , wherein the second solution comprises a particle-forming material in a second solvent. 
     
     
         4 . The system of  claim 1 , wherein the first solution comprises a nucleic acid in a first solvent and the second solution comprises lipid particle-forming materials in a second solvent. 
     
     
         5 . The system of  claim 1 , wherein the first mixer comprises a mixing region comprising a microfluidic mixer configured to mix the first solution and the second solution to provide the nanoparticle solution formed from mixing of the first solution and the second solution. 
     
     
         6 . The system of  claim 5 , wherein the first mixer is a chaotic advection mixer. 
     
     
         7 . The system of  claim 5 , wherein the mixing region comprises a herringbone mixer. 
     
     
         8 . The system of  claim 4 , wherein the mixing region has a hydrodynamic diameter of about 20 microns to about 300 microns. 
     
     
         9 . The system of  claim 1 , wherein the first mixer is sized and configured to mix the first solution and the second solution at a Reynolds number of less than 1000. 
     
     
         10 . The system of  claim 1 , wherein the microfluidic chip is sterile. 
     
     
         11 . The system of  claim 1 , further comprising a plurality of mixers, each including a first inlet, a first inlet microchannel, a second inlet, a second inlet microchannel, a mixing microchannel, a mixer outlet, and a chip outlet, wherein the plurality of mixers includes the first mixer. 
     
     
         12 . The system of  claim 11 , wherein the plurality of mixers are within a plurality of microfluidic chips. 
     
     
         13 . The system of  claim 11 , wherein the system further comprises a first manifold configured to receive the first solution from the first solution reservoir and distribute the first solution to the first inlets of the plurality of mixers. 
     
     
         14 . The system of  claim 11 , wherein the system further comprises a second manifold configured to receive the second solution from the second solution reservoir and distribute the second solution to the second inlets of the plurality of mixers. 
     
     
         15 . The system of  claim 11 , wherein the system further comprises a third manifold configured to receive and combine the nanoparticle solution from the chip outlets of the plurality of mixers and direct it in a single channel towards the system outlet. 
     
     
         16 . The system of  claim 11 , wherein the system further comprises:
 a first manifold configured to receive the first solution from the first solution reservoir and distribute the first solution to the first inlets of the plurality of mixers;   a second manifold configured to receive the second solution from the second solution reservoir and distribute the second solution to the second inlets of the plurality of mixers; and   a third manifold configured to receive and combine the nanoparticle solution from the chip outlets of the plurality of mixers and direct it in a single channel towards the system outlet.   
     
     
         17 . The system of  claim 11 , wherein the plurality of mixers are within the microfluidic chip. 
     
     
         18 . The system of  claim 11 , wherein at least a portion of the plurality of mixers are parallelized mixers, arranged in parallel, wherein each of the portion of plurality of mixers has a mixer outlet in fluid communication with the system outlet. 
     
     
         19 . The system of  claim 18 , wherein the parallelized mixers are arranged in a stacked configuration on the microfluidic chip. 
     
     
         20 . The system of  claim 18 , wherein the parallelized mixers are arranged in a horizontal configuration, in substantially the same plane, on the microfluidic chip. 
     
     
         21 . The system of  claim 18 , wherein the parallelized mixers are arranged in both a horizontal configuration and a stacked configuration on the microfluidic chip. 
     
     
         22 . The system of  claim 1 , further comprising a dilution element, wherein the dilution element comprises:
 a third continuous flow fluid driver, configured to continuously drive a dilution solution from a dilution solution reservoir into the system, via a dilution channel, in between the chip outlet and the system outlet.   
     
     
         23 . The system of  claim 1 , further comprising a waste outlet in fluid communication with a waste valve in between the chip outlet and the system outlet, wherein the waste valve is configured to controllably direct fluid towards the waste outlet. 
     
     
         24 . The system of  claim 1 , wherein the first continuous flow fluid driver and the second continuous flow fluid driver are independently selected from the group consisting of a positive displacement pump, a centrifugal pump, and a pressure driven pump. 
     
     
         25 . The system of  claim 1 , wherein the system includes a disposable fluidic path. 
     
     
         26 . The system of  claim 25 , wherein the disposable fluidic path includes a disposable microfluidic chip, a disposable first pump head of the first continuous flow pump, a disposable second pump head of the second continuous flow pump, and a disposable system outlet. 
     
     
         27 . The system of  claim 26 , wherein the disposable first pump head and the disposable second pump head are made of a material independently selected from the group consisting of stainless steel, polymer, titanium, and ceramic. 
     
     
         28 . The system of  claim 25 , wherein every surface touched by the first solution, the second solution, and the nanoparticle solution are disposable. 
     
     
         29 . The system of  claim 1 , wherein the system has a footprint area of 1 m 2  or less. 
     
     
         30 . The system of  claim 29 , wherein the system has a production volume of at least 0.76 L of nanoparticle solution per hour. 
     
     
         31 . The system of  claim 1 , further comprising a pulse dampening mechanism configured to minimize flow pulsation from the first continuous flow fluid driver, the second continuous flow fluid driver, or both. 
     
     
         32 . A sterile package comprising a sterile microfluidic chip according to any of the preceding claims sealed within the sterile package. 
     
     
         33 . A method of forming nanoparticles, comprising flowing a first solution and a second solution through a system according to any of the preceding claims and forming a nanoparticle solution in the first mixer of the microfluidic chip. 
     
     
         34 . The method of  claim 33 , wherein the system comprises a plurality of mixers and the method further comprises flowing the first solution and the second solution through the plurality of mixers to form the nanoparticle solution, wherein the plurality of mixers includes the first mixer. 
     
     
         35 . The method of  claim 34 , wherein the plurality of mixers are contained within a plurality of microfluidic chips. 
     
     
         36 . The method of  claim 34 , wherein the plurality of mixers are contained within a single microfluidic chip.