Pharmaceutical Nanotechnology - Volume 7, Issue 6, 2019

Background: Microfluidics is becoming increasingly of interest as a superior technique for the synthesis of nanoparticles, particularly for their use in nanomedicine. In microfluidics, small volumes of liquid reagents are rapidly mixed in a microchannel in a highly controlled manner to form nanoparticles with tunable and reproducible structure that can be tailored for drug delivery. Both polymer and lipid-based nanoparticles are utilized in nanomedicine and both are amenable to preparation by microfluidic approaches. Aim: Therefore, the purpose of this review is to collect the current state of knowledge on the microfluidic preparation of polymeric and lipid nanoparticles for pharmaceutical applications, including descriptions of the main synthesis modalities. Of special interest are the mechanisms involved in nanoparticle formation and the options for surface functionalisation to enhance cellular interactions. Conclusion: The review will conclude with the identification of key considerations for the production of polymeric and lipid nanoparticles using microfluidic approaches.

Background: Solid lipid nanoparticles offer a range of advantages as delivery systems but they are limited by effective manufacturing processes. Objective: In this study, we outline a high-throughput and scalable manufacturing process for solid lipid nanoparticles. Methods: The solid lipid nanoparticles were formulated from a combination of tristearin and 1,2-Distearoyl-phosphatidylethanolamine-methyl-polyethyleneglycol conjugate-2000 and manufactured using the M-110P Microfluidizer processor (Microfluidics Inc, Westwood, Massachusetts, US). Results: The manufacturing process was optimized in terms of the number of process cycles (1 to 5) and operating pressure (20,000 to 30,000 psi). The solid lipid nanoparticles were purified using tangential flow filtration and they were characterized in terms of their size, PDI, Z-potential and protein loading. At-line particle size monitoring was also incorporated within the process. Our results demonstrate that solid lipid nanoparticles can be effectively manufactured using this process at pressures of 20,000 psi with as little as 2 process passes, with purification and removal of non-entrapped protein achieved after 12 diafiltration cycles. Furthermore, the size could be effectively monitored at-line to allow rapid process control monitoring and product validation. Conclusion: Using this method, protein-loaded solid lipid nanoparticles containing a low (1%) and high (16%) Pegylation were manufactured, purified and monitored for particle size using an at-line system demonstrating a scalable process for the manufacture of these nanoparticles.

Background: A key challenge in the manufacturing of polymeric colloids is producing nanoparticles with good batch-to-batch consistency. Objective: Develop a robust microfluidics method for the preparation of PEG-PLGA nanoparticles using dimethyl sulfoxide (DMSO) as the organic phase solvent for the encapsulation of DMSO soluble agents. Methods: Microfluidic process parameters, total flow rate (10 mL/min), flow rate ratio (1:1) of the aqueous phase and the organic polymer solution, and polymer concentration (5 mg/ml). Polyvinyl alcohol (PVA) or human serum albumin (HSA) was included in the aqueous phase. Dynamic light scattering and transmission electron microscopy were used to investigate the size and morphology of particles. Results: PLGA nanoparticles made using DMSO with the aqueous solvent containing PVA (2%) had an average size of 60 nm while PLGA-PEG nanoparticles made with and without PVA (2%) had an average size of 70 and 100 nm, respectively. PLGA-PEG nanoparticles generated with or without PVA had a high batch-to-batch coefficient of variation for the particle size of 20% while for PLGA nanoparticles with PVA it was 4%. HSA added to the aqueous phase reduced the size and the zeta potential of PEG-PLGA nanoparticles as well the batch-to-batch coefficient of variation for particle size to < 5%. Nanoparticles were stable in solution and after lyophilized in the presence of sucrose. Conclusion: Albumin was involved in the self-assembly of PEG-PLGA nanoparticles altering the physicochemical properties of nanoparticles. Adding protein to the aqueous phase in the microfluidic fabrication process may be a valuable tool for tuning the properties of nanoparticles and improving batch-to-batch consistency.

Objective: To compare the characteristics of rutin-loaded PLGA (poly(lactic-coglycolic acid)) nanoparticles prepared using a single emulsion evaporation method (bulk method) and a nanoprecipitation method using microfluidics. Methods: Rutin-loaded PLGA nanoparticles were produced using different methods and characterized for size, zeta potential, entrapment efficiency (EE) and drug loading (DL). A design of experiments approach was used to identify the effect of method parameters to optimize the formulation. DSC was used to investigate the solid-state characteristics of rutin and PLGA and identify any interactions in the rutin-loaded PLGA nanoparticles. The release of rutin from PLGA nanoparticles was examined in biorelevant media and phosphate buffer (PBS). Results: The optimal formulation of rutin-loaded PLGA nanoparticles produced using a microfluidics method resulted in a higher entrapment efficiency of 34 ± 2% and a smaller size of 123 ± 4 nm compared to a bulk method (EE 27 ± 1%, size 179 ± 13 nm). The solidstate of rutin and PLGA changed from crystalline to amorphous with the preparation of rutin- loaded PLGA nanoparticles. More importantly, using microfluidics, rutin released faster from rutin-loaded PLGA nanoparticles in biorelevant media and PBS with higher burst release compared to the rutin release from the nanoparticles prepared by using the bulk method. Conclusion: Rutin can be encapsulated in nanoparticles formulated with different methods with mean sizes of less than 200 nm. Microfluidics produced more uniform rutin-loaded PLGA nanoparticles with a higher EE, DL and faster release compared to a bulk production method.

Background: Cubosomes are highly ordered self-assembled lipid particles analogous to liposomes, but with internal liquid crystalline structure. They are receiving interest as stimuli responsive delivery particles, but their preparation typically requires high energy approaches such as sonication which is not favourable in many applications. Objective: Here we investigated the impact of microfluidic preparation on particle size distribution and internal structure of cubosomes prepared from two different lipid systems, phytantriol and glyceryl monooleate (GMO). Methods: The impact of relative flow rates of the aqueous and organic streams, the total flow rate and temperature were investigated in a commercial microfluidic system. The particle size distribution and structure were measured using dynamic light scattering and small angle X-ray scattering respectively. Results: Phytantriol based particles were robust to different processing conditions, while cubosomes formed using GMO were more sensitive to composition both locally and globally, which reflects their preparation using other techniques. Conclusion: Thus, in summary microfluidics represents a reproducible and versatile method to prepare complex lipid particle dispersions such as cubosomes.