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

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.

Liposomalization of SN-38 as active metabolite of CPT-11.

Although many drugs have been developed for the treatment of disease, some drugs have complications such as adverse effects, and antitumor agents should target tumors or cells more selectively. It is therefore necessary to develop drug delivery systems, and liposomes are reportedly useful as an effective drug carrier. An antitumor agent, CPT-11, inhibits DNA synthesis by the inhibition of topoisomerase1 and has a strong antitumor activity. SN-38 is converted from CPT-11 as an active metabolite by carboxylesterase in the liver. As SN-38 is insoluble, it has not been applied at the clinical stage as an injection. It is expected that SN-38 liposomalization may increase its usefulness in cancer chemotherapy. Our purpose is to have a clinical application of SN-38 by a novel method of liposomalization to expand the application for the other insolubility drugs. As SN-38 is hydrophobic, SN-38-trapped liposome preparation was attempted using the Bangham method, which is effective for general preparation. However, a high ratio of SN-38 trapped in liposome was not achieved, and this was not improved by the freezing-thawing method or the freeze-drying method. On the other hand, the ratio of SN-38 trapped in liposome by the modified remote loading method was about 4 times that by the Bangham method, and the ratio by the film loading method, novel method of liposomal preparation, reached 2 times and 8 times that by the modified remote loading method and Bangham method, respectively, showing a remarkable increase. In conclusion, it was suggested that the preparation of SN-38 liposome using the film loading method effectively entraps SN-38. Thus, it is expected that SN-38 liposome can be applied as an injection. This preparation method is useful if application is possible in the other insolubility drugs.