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Pharmaceutics 2018, 10(2), 60; https://doi.org/10.3390/pharmaceutics10020060

A Repurposed Drug for Brain Cancer: Enhanced Atovaquone Amorphous Solid Dispersion by Combining a Spontaneously Emulsifying Component with a Polymer Carrier

1
Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA
2
Division of Pharmacotherapy, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA
3
Institute for Drug Development, Cancer Therapy and Research Center (CTRC), University of Texas Health San Antonio, 7979 Wurzbach Dr., San Antonio, TX 78229, USA
*
Authors to whom correspondence should be addressed.
Received: 24 April 2018 / Revised: 14 May 2018 / Accepted: 16 May 2018 / Published: 19 May 2018
(This article belongs to the Special Issue Pharmaceutical Applications of Hot-melt Extrusion)
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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. View Full-Text
Keywords: atovaquone; hot-melt extrusion; amorphous solid dispersion; supersaturation; glioblastoma multiforme; repurposing drugs atovaquone; hot-melt extrusion; amorphous solid dispersion; supersaturation; glioblastoma multiforme; repurposing drugs
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Takabe, H.; Warnken, Z.N.; Zhang, Y.; Davis, D.A.; Smyth, H.D.C.; Kuhn, J.G.; Weitman, S.; Williams III, R.O. A Repurposed Drug for Brain Cancer: Enhanced Atovaquone Amorphous Solid Dispersion by Combining a Spontaneously Emulsifying Component with a Polymer Carrier. Pharmaceutics 2018, 10, 60.

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