Title: In-vitro Two Step Dissolution Study of Docetaxel Granules in Fed Media

Presenter: Chaitanya Kasim Authors: Chaitanya Kasim, OMS-II, Dr. Brijesh Shah, Ph.D, Dr. Xiaowei Dong, Ph.D Title: In-vitro Two Step Dissolution Study of Docetaxel Granules in Fed Media Background: Lung cancer is the leading cause of death in America amongst all cancer related deaths. The conventional treatment for lung cancer is with Docetaxel (DTX), which works by inhibiting microtubule formation and has shown to significantly slow lung cancer progression. Typical administration of DTX is based on administering high doses of chemotherapeutic drugs at low frequency; however, this treatment method yields a poor 5-year survival outcome. Specifically, DTX is administered intravenously (IV) due to its low oral bioavailability. IV administration, however, is taxing on the patient, so better therapy modalities are needed. Recent studies suggest that metronomic therapy, administering low doses of a drug at high frequency, may lead to better survival outcomes. Our lab explored in situ self-assembling nanoparticle (ISNP) granule composed of lipids and surfactant as a potential method of drug delivery for metronomic therapy. The aim of this study is to determine the optimal Lipid: Surfactant ratio and composition for high DTX drug release. Hypothesis: We hypothesize that the ISNP granule composed of 1:1 lipid: surfactant ratio will lead to the highest drug release. Methods: Previous studies have shown that ISNP granules were able to deliver significant drug concentration to lung tissue in vivo but failed to demonstrate these results in vitro. To reflect this discrepancy between in vivo and in vitro studies, our lab developed new protocols that correlated with physiological pH changes during digestion known as "Fed Media". Our lab formulated DTX ISNP granule composed of different ratios of lipid-Miglyol 812 (M) and surfactant- TPGS (T) and added to Fed Media. Samples were taken at different timepoints and drug release was measured via HPLC. We then formulated granules composed of different lipids (Cap200 and PG8 backbone) and measured its drug release. Results: The M:T 1:1 formulation led to the highest drug release. As expected, the blank granules led to a lower or similar release when compared to pure DTX powder. However, there was an interesting result, the DTX release for M:T ratio 0:1 is close to M:T 1:1. This was surprising as it showed that surfactants played an important role when prior emphasis was placed on lipids. For different lipid compositions, Cap200 is showing a higher drug release compared to PG8 backbone. Conclusion: The results validate the hypothesis that 1:1 M:T ratio will lead to the highest drug release. However, the 0:1 M:T ratio provides interesting avenues for research. The role of surfactants in improving DTX solubility needs to be explored further. One theory is that the granule formulation process might by playing a role in improving solubility. Future directions for this study include exploring different diester lipid backbones and see how it effects drug release.