Water-in-oil (w/o) microemulsion for oral delivery of doxorubicin

다국어 초록 (Multilingual Abstract)

Purpose: Although doxorubicin (DOX) is a potent anticancer drug, development of its oral formulation has been hindered by its limited intestinal absorption and low oral bioavailability. The limited intestinal absorption via the paracellular pathway may be the primary cause of the low oral bioavailability of DOX. In this study, medium chain glycerides-based colloidal systems were formulated to enhance the intestinal paracellular absorption of DOX thereby improving its oral delivery.
Methods: The DOX formulations prepared by the construction of pseudo-ternary phase diagram were characterized in terms of their droplet size distribution, viscosity, drug loading and drug release. Further evaluation was conducted by an in vitro Caco-2 cell transport study as well as in situ / in vivo intestinal absorption, bioavailability and toxicity studies.
Results: The water-in-oil (w/o) microemulsion systems consisting of Captex 355 (oil), Span 80/ Tween 80 or Capmul MCM/Labrasol (surfactant mixture) and water were developed for oral delivery of DOX. Compared with DOX solution, these formulations enhanced the absorptive transport of DOX across Caco-2 cell monolayers at least partly due to the paracellular-enhancing effects of their lipidic components. Moreover, the in situ intestinal absorption and in vivo oral bioavailability of DOX in rats were markedly enhanced. In addition, no discernible damage was observed in the rat jejunum after oral administration of these DOX formulations while the cardiac toxicity was significantly reduced when compared with intravenous DOX solution.
Conclusions: The medium chain glycerides-based colloidal system prepared in this study represents a potentially effective oral delivery system for DOX.

목차 (Table of Contents)

• ABSTRACT i
• CONTENTS iii
• List of Tables v
• List of Figures vi
• 1. Introduction 1
• 2. Materials and methods 5
• 2.1. Materials 5
• 2.2. Construction of Pseudo-Ternary Phase Diagrams 6
• 2.3. Determination of maximum loading content and preparation of DOX formulations 6
• 2.4. Characterization of DOX Formulations 7
• 2.4.1. Mean Droplet Size and Distribution 7
• 2.4.2. Viscosity 7
• 2.4.3. Transmission Electron Microscopy 8
• 2.4.4. Changes of DOX Formulations after Dilution 8
• 2.5. In vitro Release Study 8
• 2.6. Caco-2 Cell Culture 9
• 2.7. In vitro Cytotoxicity Test in Caco-2 Cells 9
• 2.8. In vitro Transport Study in Caco-2 Cell Monolayers 10
• 2.9. Animals 11
• 2.10. In situ Closed Loop Study in Rats 12
• 2.11. In vivo Pharmacokinetic Study in Rats 13
• 2.12. In vivo Toxicity Test in Mice and Rats 13
• 2.13. HPLC Analysis of DOX 14
• 2.14. Pharmacokinetic Analysis 15
• 2.15. Statistical Analysis 16
• 3. Results 17
• 4. Discussion 22
• 5. Conclusion 27
• 6. References 28
• 국문초록 48