Development of Novel Coated Tegafur Pellets by Extrusion-Spheronization: A Targeted and Localized Delivery System for Colon Cance

Tegafur (TF), the oral prodrug of 5-Fluorouracil (5-FU) acts as a drug depot that gradually releases 5-FU. Liver microsomal P450 enzyme CYP 2A6 is primarily responsible for this metabolism; however, 5-FU is also degraded by dihydropyrimidine dehydrogenase (DPD) in the liver, significantly reducing its bioavailability. To overcome DPD degradation and to minimize 5-FU systemic toxicity, a localized (topical) and targeted TF delivery to the colon was investigated. Chapter 2 focuses on the 5-FU and TF uptake and cytotoxicity studies using HT-29, HT-29/B6 and CACO-2 human gastrointestinal cell line models. HT-29, HT-29/B6 and CACO-2 expressed CYP 2A6, but had different TF and 5-FU sensitivity, which lead to investigating the effect of cell cycle (proliferation) on the uptake of TF and 5-FU. CYP 2A6 expression in the three cell line models suggests that TF (the prodrug) can be activated at the very site of desired action (cancer cells).;It was reported that increased TJ permeability of colon epithelium and decreased barrier function precede the development of colon tumors, and that TJ leakiness was significantly higher in diseased tissue when compared to TJ of normal colon. In Chapter 3, 5-FU and TF permeability across HT-29/B6 and CACO-2 mono-layer models and HT-29 multicellular layer models was investigated. Flux data revealed that TF and 5-FU across undifferentiated and highly differentiated cell culture models displayed specific cell line-dependency and concentration-dependency. TF had dramatic permeation across poorly differentiated colon cancer models (HT- 29), which suggests deep penetration into those solid tumors from the apical side. Thus, the feasibility of colon specific delivery of TF for its use in the topical localized treatment of colon cancer may be possible. Efficient flux of TF should occur due to its high localized concentration in the apical surface of the colon mucosa.;Chapter 4 explores the manufacturing of TF pellets, based on the scale-up of modified CODES(TM) technology. Core pellets containing TF and lactulose were manufactured by extrusion-spheronization. An experimental design was laid out using Design-ExpertRTM 10 to study the influence of certain formulation and processing variables. ANOVA was used to optimize the responses. Based on the results of the experimental design studies, it was concluded that it is not feasible to produce TF core pellets containing lactulose at the required level to achieve colon specific release with a usable yield above 45%. Thus, in Chapter 5, rugged and spherical TF containing core pellets were successfully manufactured through the process of extrusion-spheronization, and coated with a lactulose coat. Model fitting for the coated pellets indicated that there was no significant polymer relaxation contribution to the release mechanism and that diffusion of dissolved drug is the principle mechanism of drug released.