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

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Abstract

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.

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ACKNOWLEDGMENTS AND DISCLOSURES

Financial support from Lonza - Pharma Biotech & Nutrition Sciences (formerly Capsugel) is gratefully acknowledged. This work was supported by the Multi-modal Australian ScienceS Imaging and Visualisation Environment (MASSIVE).

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Authors and Affiliations

  1. Monash Institute of Pharmaceutical Sciences, Melbourne, Australia

    Dallas B. Warren, Shadabul Haque, Mitchell P. McInerney, Karen M. Corbett, Endri Kastrati, Christopher J.H. Porter, David K. Chalmers & Colin W. Pouton

  2. Lonza Pharma, Biotech & Nutrition, Melbourne, Australia

    Leigh Ford & Hywel D. Williams

  3. Lonza Pharma, Biotech & Nutrition, Strasbourg, France

    Vincent Jannin & Hassan Benameur

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  1. Dallas B. Warren
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  2. Shadabul Haque
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Correspondence to Dallas B. Warren, David K. Chalmers or Colin W. Pouton.

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Animations of Final Frames

Animations of Sandimmune® and Neoral® in 90% water, 90% fasted buffer, 90% fed buffer conditions corresponding to Fig. 7, and digested formulations in 90% water unionized and ionized corresponding to Fig. 8 are included. The molecular representations are; cyclosporine A atoms = spheres (color cyan = carbon, red = oxygen, white = polar hydrogen), alkane chains = orange solvent accessible surface, surfactants = red licorice, glycerides = orange licorice, fatty acids = brown licorice, bile salts = green licorice, and phospholipid = yellow licorice. Solvents (water, ethanol and propylene glycol) have been omitted for clarity.

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Warren, D.B., Haque, S., McInerney, M.P. et al. Molecular Dynamics Simulations and Experimental Results Provide Insight into Clinical Performance Differences between Sandimmune® and Neoral® Lipid-Based Formulations. Pharm Res 38, 1531–1547 (2021). https://doi.org/10.1007/s11095-021-03099-5

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