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Continuous Production of Stable Polymeric Nanoparticles for Oral Drug Delivery

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Title: Continuous Production of Stable Polymeric Nanoparticles for Oral Drug Delivery
Author(s): Shen, Hao
Advisor(s): Liu, Ying
Contributor(s): Murad, Sohail; Wedgewood, Lewis E.; Hong, Seungpyo; Perez-Salas, Ursula
Department / Program: Chemical Engineering
Graduate Major: Chemical Engineering
Degree Granting Institution: University of Illinois at Chicago
Degree: PhD, Doctor of Philosophy
Genre: Doctoral
Subject(s): polymeric nanoparticles: oral drug delivery flash nanoprecipitation multi-inlet vortex mixer spray drying chemoprevention, morphine tolerance and dependence
Abstract: Minimal bioavailability of hydrophobic compounds limits their biomedical and biological applications. In this thesis, we have developed a continuous and scalable process to generate stable polymeric nanoparticles encapsulating hydrophobic drugs (such as beta-carotene, SR13668, and curcumin), based upon our understanding of the competitive kinetics of flash nanoprecipitation and spray drying. A custom-designed multi-inlet vortex mixer (MIVM) was employed to implement the process of flash nanoprecipitation (FNP). Flow patterns in the MIVM were microscopically visualized by mixing iron nitrate and potassium thiocyanate to precipitate Fe(SCN)x(3-x)+. Effects of physical parameters (including Reynolds number, supersaturation rate, interaction force, and drug loading rate) on size distribution of the nanoparticle suspensions were investigated. The prepared nanoparticle suspensions through FNP were then spray dried to (1) achieve particle long-term stability, (2) quickly remove organic solvents used for nanoprecipitation, and (3) be able to conveniently adjust the nanoparticle concentration prior to use. Excipients such as sucrose, trehalose and leucine were used as "spacers" to prevent permanent aggregation during the spray drying process. The optimized condition was achieved by thoughtful consideration of the glass transition temperatures of the polymers and transport processes of evaporation and particle diffusion. The nanoparticles were then re-suspended prior to animal tests. Bioavailability and bioactivity of the nanoparticles were verified in animals for two compounds when orally dosed – SR13668 (a cancer preventive agent) and curcumin (a potential agent to attenuate morphine tolerance and dependence). Enhanced bioavailability of PLGA-SR13668 nanoformulation was observed in mice and beagle dogs, compared with formulations of Labrasol® and neat drug in 0.5% methylcellulose. Mice behavioral studies, include tail-flick, hot plate, and precipitate withdrawal experiments, were conducted to demonstrate the effects of curcumin nanoformulation on attenuating morphine tolerance and dependence. Significant analgesia was observed in both tail-flick and hot plate experiments, while free curcumin at same concentration showed minimal effect.
Issue Date: 2013-10-31
Genre: thesis
Rights Information: Copyright 2013 Hao Shen
Date Available in INDIGO: 2015-11-01
Date Deposited: 2013-08

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