Towards a Continuous Manufacturing Process of Protein-Loaded Polymeric Nanoparticle Powders

Abstract

To develop a scalable and efficient process suitable for the continuous manufacturing of poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing ovalbumin as the model protein. PLGA nanoparticles were prepared using a double emulsification spray-drying method. Emulsions were prepared using a focused ultrasound transducer equipped with a flow cell. Either poly(vinyl alcohol) (PVA) or poloxamer 407 (P-407) was used as a stabilizer. Aliquots of the emulsions were blended with different matrix excipients and spray dried, and the yield and size of the resuspended nanoparticles was determined and compared against solvent displacement. Nanoparticle sizes of spray-dried PLGA/PVA emulsions were independent of the matrix excipient and comparable with sizes from the solvent displacement method. The yield of the resuspended nanoparticles was highest for emulsions containing trehalose and leucine (79%). Spray drying of PLGA/P-407 emulsions led to agglomerated nanoparticles independent of the matrix excipient. PLGA/P-407 nanoparticles pre-formed by solvent displacement could be spray dried with limited agglomeration when PVA was added as an additional stabilizer. A comparably high and economically interesting nanoparticle yield could be achieved with a process suitable for continuous manufacturing. Further studies are needed to understand the robustness of a continuous process at commercial scale.

Keywords: PLGA nanoparticles; continuous manufacturing; focused ultrasound; protein delivery; spray drying.

Fig. 1

Resulting nanoparticle sizes after spray drying of PLGA/PVA double emulsions with and without the addition of different matrix excipients. Spray-dried powders were reconstituted in purified water, then aggregates were removed by filtration, and particle size distribution was measured by dynamic light scattering. Nanoparticles precipitated by solvent displacement without spray drying served as the control. Measurements were done in triplicate, RSD < 0.5%

Fig. 2

Resulting nanoparticle yield after spray drying of PLGA/PVA double emulsions with and without the addition of different matrix excipients. Nanoparticles were isolated from the matrix after reconstitution of the complete batch in purified water, then aggregates were removed by filtration, and the mass was determined after drying

Fig. 3

Resulting nanoparticle sizes after spray drying of PLGA/P-407 double emulsions with and without the addition of different matrix excipients. Spray-dried powders were reconstituted in purified water, then aggregates were removed by filtration, and particle size distribution was measured by dynamic light scattering. Nanoparticles precipitated by solvent displacement without spray drying served as the control. Measurements were done in triplicate, RSD < 0.5%

Fig. 4

Resulting nanoparticle yield after spray drying of PLGA/P-407 double emulsions with and without the addition of different matrix excipients. Nanoparticles were isolated from the matrix after reconstitution of the complete batch in purified water, then aggregates were removed by filtration, and the mass was determined after drying. The nanoparticle yield with K30 was too low to determine by weighing and, as such, is reported as 0