A repurposed drug for brain cancer: Enhanced atovaquone amorphous solid dispersion by combining a spontaneously emulsifying component with a polymer carrier

Hiroyuki Takabe, Zachary N. Warnken, Yajie Zhang, Daniel A. Davis, Hugh D.C. Smyth, John G. Kuhn, Steve Weitman, Robert O. Williams

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Glioblastoma multiforme (GBM) is the most common and lethal central nervous system tumor. Recently, atovaquone has shown inhibition of signal transducer and activator transcription 3, a promising target for GBM therapy. However, it is currently unable to achieve therapeutic drug concentrations in the brain with the currently reported and marketed formulations. The present study sought to explore the efficacy of atovaquone against GBM as well as develop a formulation of atovaquone that would improve oral bioavailability, resulting in higher amounts of drug delivered to the brain. Atovaquone was formulated as an amorphous solid dispersion using an optimized formulation containing a polymer and a spontaneously emulsifying component (SEC) with greatly improved wetting, disintegration, dispersibility, and dissolution properties. Atovaquone demonstrated cytotoxicity against GBM cell lines as well as provided a confirmed target for atovaquone brain concentrations in in vitro cell viability studies. This new formulation approach was then assessed in a proof-of-concept in vivo exposure study. Based on these results, the enhanced amorphous solid dispersion is promising for providing therapeutically effective brain levels of atovaquone for the treatment of GBM.

Original languageEnglish (US)
Article number60
JournalPharmaceutics
Volume10
Issue number2
DOIs
StatePublished - May 19 2018

Keywords

  • Amorphous solid dispersion
  • Atovaquone
  • Glioblastoma multiforme
  • Hot-melt extrusion
  • Repurposing drugs
  • Supersaturation

ASJC Scopus subject areas

  • Pharmaceutical Science

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