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Preparation and Evaluation of Mebendazole Microemulsion for Intranasal Delivery: an Alternative Approach for Glioblastoma Treatment

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Abstract

Although mebendazole (MBZ) has demonstrated antitumor activity in glioblastoma models, the drug has low aqueous solubility and therefore is poorly absorbed. Considering that other strategies are needed to improve its bioavailability, the current study was aimed to develop and evaluate novel microemulsions of MBZ (MBZ-NaH ME) for intranasal administration. MBZ raw materials were characterized by FTIR, DSC, and XDP. Subsequently, the raw material that contained mainly polymorph C was selected to prepare microemulsions. Two different oleic acid (OA) systems were selected. Formulation A was composed of OA and docosahexaenoic acid (3:1% w/w), while formulation B was composed of OA and Labrafil M2125 (1:1% w/w). Sodium hyaluronate (NaH) at 0.1% was selected as a mucoadhesive agent. MBZ MEs showed a particle size of 209 nm and 145 nm, respectively, and the pH was suitable for nasal formulations (4.5–6.5). Formulation B, which showed the best solubility and rheological behavior, was selected for intranasal evaluation. The nasal toxicity study revealed no damage in the epithelium. Furthermore, formulation B improved significantly the median survival time in the orthotopic C6 rat model compared to the control group. Moreover, NIRF signal intensity revealed a decrease in tumor growth in the treated group with MBZ-MaH ME, which was confirmed by histologic examinations. Results suggest that the intranasal administration of mebendazole-loaded microemulsion might be appropriated for glioblastoma treatment.

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Acknowledgments

The authors are grateful to Gateffosse (Químicos Lyontec) for the donation of Transcutol HP, Labrafac, Labrafil M 2125, Labrafil and Peceol excipients, and to Croda Inc. (Química Croda) for the donation of super-refined oleic acid and docosahexaenoic acid. We greatly appreciate the support provided by the staff at USAII UNAM to characterize mebendazole.

Funding

This study was financially supported by UNAM-DGAPA-PAPIIT: IN223817. Student grant (257882) was provided to Julio Mena by CONACYT during the study.

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Authors and Affiliations

  1. Programa de Maestría y Doctorado en Ciencias Químicas, Universidad Nacional Autónoma de México, 04510, México City, Mexico

    Julio Mena-Hernández

  2. Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, 04510, México City, Mexico

    Julio Mena-Hernández, Helgi Jung-Cook & Lourdes Mayet-Cruz

  3. Laboratorio de Neuropsicofarmacología, Instituto Nacional de Neurología y Neurocirugía” Manuel Velasco Suárez”, 14269, Mexico City, Mexico

    Helgi Jung-Cook

  4. Laboratorio de Farmacología, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico

    Monserrat Llaguno-Munive & Patricia García-López

  5. Laboratorio de Investigación y Posgrado en Tecnología Farmacéutica, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, 54740, Edo de Mex, Mexico

    Adriana Ganem-Rondero

  6. Departamento de Ingeniería Química/USIP, Facultad de Química, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico

    Simón López-Ramírez & Fernando Barragán-Aroche

  7. Unidad de Experimentación Animal, Facultad de Química, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico

    Marisol Rivera-Huerta

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  1. Julio Mena-Hernández
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Correspondence to Helgi Jung-Cook.

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Mena-Hernández, J., Jung-Cook, H., Llaguno-Munive, M. et al. Preparation and Evaluation of Mebendazole Microemulsion for Intranasal Delivery: an Alternative Approach for Glioblastoma Treatment. AAPS PharmSciTech 21, 264 (2020). https://doi.org/10.1208/s12249-020-01805-x

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