Molecular Dynamics Simulations and Experimental Results Provide Insight into Clinical Performance Differences between Sandimmune® and Neoral® Lipid-Based Formulations

Dallas B. Warren, Shadabul Haque, Mitchell P. McInerney, Karen M. Corbett, Endri Kastrati, Leigh Ford, Hywel D. Williams, Vincent Jannin, Hassan Benameur, Christopher J.H. Porter, David K. Chalmers, Colin W. Pouton

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Objective: Molecular dynamics (MD) simulations provide an in silico method to study the structure of lipid-based formulations (LBFs) and the incorporation of poorly water-soluble drugs within such formulations. In order to validate the ability of MD to effectively model the properties of LBFs, this work investigates the well-known cyclosporine A formulations, Sandimmune® and Neoral®. Sandimmune® exhibits poor dispersibility and its absorption from the gastrointestinal tract is enhanced when administered after food, whereas Neoral® disperses comparatively well and shows no food effect. Methods: MD simulations were performed of both LBFs to investigate the differences observed in fasted and fed conditions. These conditions were also tested using an in vitro experimental model of dispersion and digestion. Results: These MD simulations were able to show that the food effect observed for Sandimmune® can be explained by large changes in drug solubilization on addition of bile. In contrast, Neoral® is well dispersed in water or in simulated fasted conditions, and this dispersion is relatively unchanged on moving to fed conditions. These differences were confirmed using dispersion and digestion in vitro experimental model. Conclusions: The current data suggests that MD simulations are a potential method to model the fate of LBFs in the gastrointestinal tract, predict their dispersion and digestion, investigate behaviour of APIs within the formulations, and provide insights into the clinical performance of LBFs. Graphical abstract: [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)1531-1547
Number of pages17
JournalPharmaceutical Research
Issue number9
Publication statusPublished - Sept 2021


  • aqueous phase behaviour
  • in vitro digestion
  • lipid-based formulation
  • molecular dynamics simulation

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