Microfluidics-based Manufacture of PEG-b-PLGA Block Copolymer Nanoparticles for the Delivery of Small Molecule Therapeutics

S.M. Garg, M. Parmar, A. Thomas, E. Ouellet, M. DeLeonardis, M. Assadian, A. Armstead, S. Ip, T.J. Leaver, A.W. Wild, R.J. Taylor, E.C. Ramsay
Precision NanoSystems Inc.,
Canada

Keywords: polymer, PEG, PLGA, block copolymer, nanoparticle, small molecule therapeutics, drug delivery vehicle, hydrophobic, nanoprecipitation, scale up

Summary:

Purpose: In recent years, numerous methods have been developed for the production of block copolymer nanoparticles as drug delivery vehicles. However, these methods pose numerous challenges in maintaining consistent nanoparticle quality, tuning size depending on the application, optimization for scale-up, and reproducibility. The NanoAssemblr™ platform is an automated microfluidics-based system that eliminates user variability and is capable of reproducible, and scalable manufacture of nanoparticles. Here, we describe the use of microfluidic mixing to manufacture PEG-b-PLGA nanoparticles using the NanoAssemblr™ Benchtop instrument. We further describe optimization strategies and investigate the physical encapsulation of a hydrophobic model drug coumarin-6. Methods: PEG-b-PLGA nanoparticles were manufactured using the NanoAssemblr™ Benchtop instrument (Precision NanoSystems Inc., Vancouver, Canada). PEG5000-b-PLGAX of varying molecular weights of the hydrophobic block (X) was dissolved in suitable organic solvents (e.g. acetone, DMSO) at desired concentrations. PEG-b-PLGA nanoparticles were formed by nanoprecipitation achieved by the rapid and controlled mixing of two-inlet fluid streams containing PEG-b-PLGA in organic solvent, and aqueous solution, through proprietary staggered herringbone mixing (SHM) apparatus. Coumarin-6 was loaded into PEG-b-PLGA nanoparticles and compared against conventional manufacturing technique. Results: Microfluidic mixing enabled the rapid and consistent manufacturing of PEG-b-PLGA nanoparticles having diameters below 100 nm. Instrument parameters such as aqueous:organic flow rate ratio and total flow rate had a significant impact on the size of the resulting nanoparticles. Increasing the molecular weight of the PLGA block from 10000 - 95000 resulted in an increase in the size of the nanoparticles from 25 - 60 nm. However, changes in the total flow rate of the instrument enabled all the nanoparticles to be tuned to a similar size of 60 nm which is difficult to control using conventional techniques. Coumarin-6 was successfully loaded into PEG-b-PLGA nanoparticles with an encapsulation efficiency of 52% w/w which was significantly higher than that obtained by co-solvent evaporation technique (34% w/w) (Table 1). The size of the nanoparticles prepared using the NanoAssemblr™ platform were smaller than that prepared using co-solvent evaporation. Conclusions: Herein, we have successfully reported the development and manufacture of PEG-b-PLGA nanoparticles encapsulated with coumarin-6 using the NanoAssemblr™ microfluidics technology. We have further demonstrated the potential of this platform in the encapsulation and delivery of small molecule therapeutics.