(M1030-02-10) Exploring the Influence of Dietary Components and Excipients on Intestinal Lymphatic Drug Absorption: Findings from an Advanced In Vitro Approach

Purpose: This investigation aims to delve into the intricate interplay between dietary components, excipients, and intestinal lymphatic drug absorption, leveraging an advanced in-vitro model. By scrutinizing the effects of various oils and excipients on lymphatic uptake via chylomicrons, we seek to unravel novel insights crucial for formulation optimization and regulatory considerations in drug development.

Methods: In this study, rifampicin (1 mg/mL) served as the model drug, administered into the donor compartment of Franz cells. The receiver compartment contained either artificial chylomicrons or a blend of these chylomicrons with another agent, maintained at 37.0 ± 0.5 °C. Different oils (olive, sesame, peanut, coconut) were scrutinized at a concentration of 2%. Separation of compartments was achieved using a PVDF membrane. Periodic sampling and subsequent HPLC analysis were employed to monitor drug absorption kinetics. Morphological characterization of artificial chylomicrons via TEM was conducted to elucidate oil distribution. Additionally, the lymphatic uptake enhancement of cannflavin A formulations with oleoyl-polyxyl-6 glycerides was evaluated using the same model.

Results: Coconut oil displayed notable enhanced release effects on rifampicin, whereas olive oil demonstrated lesser impact, yielding a 3.5-fold increase. Initially, sesame oil mimicked the behavior of olive oil but eventually matched the release profile of peanut oil, resulting in a 1.5-fold increase in uptake. Emulsification of all oils into the artificial chylomicrons was observed, creating a carrier area as confirmed by TEM analysis. The superior performance of coconut oil was attributed to its heightened emulsification capacity. Furthermore, cannflavin A formulations incorporating oleoyl-polyxyl-6 glycerides showcased augmented lymphatic uptake in the model.

Conclusion: In contrast to medium-chain-rich coconut oil, other oils containing long-chain fatty acids (LCFs) closely mirrored their in-vivo performance, underscoring the significance of fatty acid chain length in lymphatic drug absorption. Moreover, the assessment of oleoyl-polyxyl-6 glycerides highlighted the practical applicability of this model in formulation optimization and regulatory evaluations for products targeting the lymphatic system. These findings offer valuable insights essential for refining drug delivery strategies and enhancing therapeutic outcomes.

Acknowledgements:

Funding: This research was funded by MITACS Accelerate Internship as part of M.Y. Ph.D. and C.O. MSc programs.


Figure 1. Demonstration of the increased in vitro lymphatic uptake of rifampicin via the developed model when 2% of different oils were added to the artificial chylomicron media. Data represent mean ± SE (n = 3). * Indicates the statistical significance (p < 0.05) between the different groups. Images of different components are from designers on Freepik.com


Figure 2. Illustartion of the increased in vitro lymphatic uptake of cannflavin A (CFA) via the developed model when an uptake enhancer (oleoyl-polyxyl-6 glycerides) was added to the artificial chylomicrons media. Data represent mean ± SD (n = 6). * Indicates the statistical significance (p < 0.05) between the different groups.