(473e) Translation of Nanoparticle Therapeutics from Laboratory Discovery to Clinical Scale: Scaled-up Production and Solidification

Authors: 
Tian, C., Princeton University
Feng, J., University of Illinois, Urbana-Champaign
Markwalter, C. E., Princeton University
Wang, L. Z., Princeton University
Armstrong, M., Princeton University
Prud'homme, R. K., Princeton University
Malaria is a major cause of mortality in the developing tropical regions and its effective low-cost therapies are in much need. Lumefantrine is a Biopharmaceutics Classification System class II drug and can be used as a cure for malaria. We have developed in the past low-cost lumefantrine encapsulated nanoparticles (NPs) using stabilizers such as zein/casein and HPMCAS via Flash Nanoprecipitation (FNP) method. A continuous production line of NPs is set up to transfer the nanoparticle production from laboratory scale to clinical level. Using mixers of three different scales, the production rate of NPs is increased from a batch of a few milligrams to a continuous production of a hundred kilograms per day. An ultrafiltration system has been constructed to increase the NP concentration after FNP, which greatly improves the NP solidification efficiency. The shear rate and transmembrane pressure of NP flow within different types of filters are carefully controlled to prevent NP aggregation and filter cake accumulation. Next, scalable and continuous spray drying was applied to NP suspension of increased concentration to obtain dried powders with long-term storage stability. The dissolution kinetics of dried NP powders are showed to be significantly improved compared to that of crystalline lumefantrine in simulated fasted and fed intestine media. These results demonstrate complete translation of therapeutic nanoparticles from laboratory discovery to large scale clinical production.
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