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theses

Lymphatic drug transport can confer bioavailability advantage by avoiding the first-pass metabolism normally observed in the portal vein hepatic route. It was reported that long chain lipid-based delivery systems can stimulate the formation of chylomicron and thus promote the lymphatic transport of drugs. In this study, a novel delta-tocopherol (δ-T) loaded Solid Lipid Nanoparticle (SLN) system was developed to investigate its effect on promoting the lymphatic transport of δ-T. The δ-T SLN was prepared with hot melt emulsification method by using glyceryl behenate (compritol®888) as the lipid phase and lecithin (PC75) as the emulsifier. Formula configuration, processing condition and loading capacity were carefully optimized. Physicochemical properties (particle size, surface charge, morphology) were also characterized. Moreover, excellent stability of the developed δ-T SLN in the gastrointestinal environment was observed by using an in vitro digestion model. Further investigations of the SLN in stimulating δ-T lymphatic transport were performed on mice without cannulation. Compared with the control group (δ-T corn oil dispersion), much lower δ-T levels in both blood and liver indicated reduced portal vein and hepatic transport of δ-T in the form of SLN. On the other hand, significantly higher concentrations of δ-T were observed in thymus, a major lymphatic tissue, indicating improved lymphatic transport of δ-T with the SLN delivery system. Finally, the far less excreted δ-T level in feces further confirmed improved lymphatic transport and overall bioavailability of δ-T by using SLN system. Nobiletin (NOB), one of most abundant polymethoxyflavones (PMFs) found in Citrus genus, has a low solubility in both water and oil at ambient temperatures. Thus it tends to form crystals when the loading exceeds its saturation level in the carrier system. This character greatly impaired its bioavailability and application. To overcome these problems, an O/W nanoemulsion was developed for NOB delivery with the presence of cremophor EL (a polyethoxylated excipient). The developed formulation can achieve a high NOB loading (0.5 wt%) with significantly reduced crystallinity and excellent physical stability. NOB’s bioaccessibility and permeation rate across the enterocytes were demonstrated to be significantly improved by the in vitro digestion model and Caco-2 cell monolayer, respectively. It is thus predictable that NOB’s bioavailability can be improved with our developed nanoemulsion formulation.

ETD_6759

M.S.

Includes bibliographical references

by Chunxin Xia

doi:10.7282/T3PN97NP

ETD graduate

The author owns the copyright to this work.