(W0930-03-20) Formulation of Freeze-Dried Self-Emulsifying Dual Oral Drug Delivery Systems in the Treatment of Breast Cancer

Purpose: Breast cancer is the third-leading cause of cancer-related deaths in women in the United States. Treatment options for breast cancer may include chemotherapy which involves the use of very potent but toxic medications, which are associated with severe adverse reactions that may further exacerbate the patient’s condition and in some cases result in death. Additionally, barriers to oral bioavailability of chemotherapies including the destabilizing acidic and enzymatic environment in the gut, poor absorption across the intestinal epithelium and the potential for hepatic first-pass metabolism limit the utility of oral administration. Combinatorial regimen involving the use of medications with different mechanisms of action have emerged as the standard treatment approach in cancer treatment. The current study combines the versatility of a self-emulsifying drug delivery system (SEDD) to entrap hydrophilic (doxorubicin; siRNA) and lipophilic (ellipticine) either separately and in combination to facilitate systemic exposure following oral administration via mannose receptor-mediated lymphatic uptake, thereby circumventing the hepatic portal system and the associated first-pass effect.

Methods: Four SEDD formulations were prepared using different ratios of Labrasol, Caproyl 90, Labrafac PG, Gellucire 44/14 and water. The optimization of the formulation was done using the pseudo ternary phase plot for determine the effective surfactant-to-oil ratios. The resulting oil and surfactant mix (i.e., oil phase) containing ellipticine was dispersed in an aqueous phase containing doxorubicin form a primary water-in-oil (w/o) emulsion. The primary emulsion then dispersed in an aqueous bulk phase containing mannosamine to form water-in-oil-in-water (w/o/w) double emulsion. The entire emulsification process was carried out in keeping with the goal of achieving self-emulsification under passive mixing condition by gentle agitation without the application of high shear. Solid dispersible formulations of the SEDD containing doxorubicin and ellipticine were obtained by subjecting the emulsions to freeze drying (18-hour cycle using Labconco FreeZone Benchtop Freeze-Dryer connected to an Edwards RV3 vacuum pump). The optimized liquid and freeze-dried formulations were characterized for stability, size and polydispersity (PDI). Thermal behavior and interactions of the lipid excipients were also investigated by differential scanning calorimetry, as well as the drug release, transcellular permeation and intracellular uptake profiles of the SEDD.

Results: Optimized ratios of Labrasol, Labrafac PG, Gelucire, and Capryol 90 faciliated the formation for stable liquid and freeze-dried w/o/w SEDD formulations. Aqueous-to-oil phase ratios (1:9, 2:8, 3:7, and 4:6) were evaluated, with 1:9 and 2:8 producing stable primary w/o emulsions. These were used to prepare w/o/w emulsions, incorporating sucrose-mannosamine as a lyoprotectant-targeting ligand complex in the external aqueous phase. Both 1:9 and 2:8 internal-to-external phase ratios formed stable emulsions, with the 2:8 ratio selected for final SEDDS development. Micrographs of the SEDD dispersions captured using an EVOS M7000 Imaging System confirmed the formation of a triphasic dispersed system having an inner water phase encapsulated within the oil phase, surrounded by an outer water phase, forming a multiple-layer water-in-oil-in-water (w/o/w) emulsion. Stable emulsification was achieved for all formulation types. SEDDs ranged in size and PDI of 90 – 347 nm, 0.005 - 0.336 respectively. Thermal analysis showed the formation of amorphous mixtures resulting from physical mixtures and freeze-dried formulations, with sustained release characteristics. Efficient cellular uptake was also observed with all four formulation types demonstrated from fluorescence micrographs.

Conclusion: A double-emulsion lipid-based self-emulsifying drug delivery (SEDD) formulation, surface-modified with mannosamine will be stable and capable of dual drug loading and facilitate oral bioavailability of both hydrophilic and lipophilic drugs through lymphatic uptake.

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Acknowledgements: None


Method of preparation of freeze-dried double emulsion SEDDS