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Supersaturable self-microemulsifying delivery systems: an approach to enhance oral bioavailability of benzimidazole anticancer drugs

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Abstract

This study explored the design of supersaturable self-microemulsifying drug delivery systems (S-SMEDDS) to address poor solubility and oral bioavailability of a novel benzimidazole derivative anticancer drug (BI). Firstly, self-microemulsifying drug delivery systems SMEDDS made of Miglyol® 812, Kolliphor® RH40, Transcutol® HP, and ethanol were prepared and loaded with the BI drug. Upon dispersion, the systems formed neutrally charged droplets of around 20 nm. However, drug precipitation was observed following incubation with simulated gastric fluid (pH 1.2). Aiming at reducing this precipitation and enhancing drug payload, supersaturable systems were then prepared by adding 1% hydroxypropyl cellulose as precipitation inhibitor. Supersaturable systems maintained a higher amount of drug in a supersaturated state in gastric medium compared with conventional formulations and were stable in simulated intestinal medium (pH 6.8). In vitro cell studies using Caco-2 cell line showed that these formulations reduced in a transient manner the transepithelial electrical resistance of the monolayers without toxicity. Accordingly, confocal images revealed that the systems accumulated at tight junctions after a 2 h exposure. In vivo pharmacokinetic studies carried out following oral administration of BI-loaded S-SMEDDS, SMEDDS, and free drug to healthy mice showed that supersaturable systems promoted drug absorption compared with the other formulations. Overall, these data highlight the potential of using the supersaturable approach as an alternative to conventional SMEDDS for improving oral systemic absorption of lipophilic drugs.

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Funding

The research leading to these results has received funding from National Research Agency (ANR), HyDNano project (ANR-18-CE18-0025-01), the PHC Pessoa Programme between ANR and Fundação para a Ciência e Tecnologia (FCT): NanoSpeed, (N° 42306YB), and from FCT project UID/Multi/04326/2019.

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Authors and Affiliations

  1. CNRS, LAGEPP UMR 5007, Univ Lyon, Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69100, Villeurbanne, France

    Annalisa Rosso, Eyad Almouazen, Valentina Andretto, Marine Leroux, Etienne Romasko, Samira Azzouz-Maache, Claire Bordes, Stéphanie Briancon & Giovanna Lollo

  2. Centre for Marine Sciences (CCMAR), Universida de Do Algarve, Campus de Gambelas, 8005-139, Faro, Portugal

    Jorge Pontes

  3. Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052, Centre Léon Bérard, CNRS UMR_5286, Univ Lyon, Université Claude Bernard, Lyon 1, Lyon, France

    Isabelle Coste, Touffic Renno & Stephane Giraud

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  1. Annalisa Rosso
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Correspondence to Giovanna Lollo.

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All animal experiments were approved by the local animal ethics of University Claude Bernard Lyon 1 and carried out in compliance with current French guidelines (authorisation number 10386).

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All authors have been personally and actively involved in substantial work leading to the paper, will take public responsibility for its content, and given their consent for publication. All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by A.R., J.P., E.R., V.A., C.B., E.A., M.L, S.A., I.C., T.R. and S.G. Manuscript was written by A.R. and G.L. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Rosso, A., Almouazen, E., Pontes, J. et al. Supersaturable self-microemulsifying delivery systems: an approach to enhance oral bioavailability of benzimidazole anticancer drugs. Drug Deliv. and Transl. Res. 11, 675–691 (2021). https://doi.org/10.1007/s13346-021-00904-x

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