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Erlotinib-Valproic Acid Liquisolid Formulation: Evaluating Oral Bioavailability and Cytotoxicity in Erlotinib-Resistant Non-small Cell Lung Cancer Cells

  • Research Article
  • Theme: Lipid-Based Drug Delivery Strategies for Oral Drug Delivery
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Abstract

Lung cancer patients develop acquired resistance to tyrosine kinase inhibitors including erlotinib (ERL) after few months of primary treatment. Evidently, new chemotherapy strategies to delay or overcome the resistance are urgently needed to improve the clinical outcome in non-small cell lung cancer (NSCLC) patients. In this paper, we have investigated the cytotoxic interaction of ERL and valproic acid (VA) in ERL-resistant NSCLC cells and developed a liquisolid formulation of ERL-VA for improving oral bioavailability of ERL. ERL is weakly basic, biopharmaceutical classification system (BCS) class II drug with extremely poor aqueous solubility while VA is a branched chain fatty acid. Ionic interaction between ERL and VA (1:2 M ratio) resulted in significant enhancement in saturation solubility of ERL at different pH range. Liquisolid formulation of ERL-VA (EVLF) developed using PEG 400 and mesoporous calcium silicate was characterized for solid state and in vitro dissolution in biorelevant dissolution medium (FaSSIF and FeSSIF). Cytotoxicity of ERL was enhanced by 2–5 folds on co-incubation with VA in HCC827/ERL cell line. Flow cytometry analysis using AnnexinV-FITC assay demonstrated that VA and ERL alone have poor apoptotic effect on HCC827/ERL cells while combination showed around 69% apoptotic cells. Western blot analysis confirmed the role of survivin in overcoming resistance. In vivo pharmacokinetic studies of EVLF in rats demonstrated a 199% relative bioavailability compared to ERL suspension. Thus, EVLF could be a promising alternative to current ERL formulations in the treatment of NSCLC.

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Acknowledgments

The authors would like to thank BASF and Tomita Pharmaceutical for kindly supplying the samples of excipients used in this study.

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Authors and Affiliations

  1. College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, 32307, USA

    Ketan Patel, Ravi Doddapaneni, Vasanthkumar Sekar, Arvind Bagde & Mandip Singh

  2. College of Pharmacy and Health Sciences, St. John’s University, Queens, New York, 11439, USA

    Ketan Patel & Manali Patki

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  1. Ketan Patel
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  2. Ravi Doddapaneni
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  4. Vasanthkumar Sekar
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Correspondence to Mandip Singh.

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Patel, K., Doddapaneni, R., Patki, M. et al. Erlotinib-Valproic Acid Liquisolid Formulation: Evaluating Oral Bioavailability and Cytotoxicity in Erlotinib-Resistant Non-small Cell Lung Cancer Cells. AAPS PharmSciTech 20, 135 (2019). https://doi.org/10.1208/s12249-019-1332-0

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  • DOI: https://doi.org/10.1208/s12249-019-1332-0

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