Development of Hot Melt Extruded Solid Dispersion of Tamoxifen Citrate and Resveratrol for Synergistic Effects on Breast Cancer Cells.

Primary standard therapy for ER-positive breast cancer being tamoxifen, newer delivery approach for enhancement of dissolution and therapeutic efficiency of tamoxifen through oral route could be a possible solution. In the present study, we investigated combination of tamoxifen (TAM) with resveratrol (RES) and observed that the combination is effective on MCF-7 breast cancer cells. To ensure co-delivery of the drugs, we explored the hot melt extrusion technique for simultaneously extruding two drugs together in order to enhance their bioavailability. As both are class II drugs with dissolution limited bioavailability, detailed formulation and process parameter analyses were carried out. Detailed characterization using microscopy, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRD) confirmed that both the drugs were molecularly dispersed in the matrix of Soluplus, CremophorRH40, and Poloxamer188, and no interactions between the ingredients were there during hot melt extrusion (HME) process. Dissolution studies confirmed that HME extrudates were able to release drug more rapidly than simple suspension formulation. Further, pharmacokinetic studies in rats were carried out for tamoxifen. Results demonstrated that extrusion significantly increased the tamoxifen oral bioavailability (p < 0.05) (Tmax = 2.00 ± 0.56 h, Cmax = 3.66 ± 1.49 μg/mL, AUC = 39.80 ± 16.24 μg h/mL, MRT = 20.49 ± 5.71) compared to the conventional suspension of tamoxifen (Tmax = 2.00 ± 0.71 h, Cmax = 2.41 ± 0.84 μg/mL, AUC = 12.82 ± 3.99 μg h/mL, MRT = 18.24 ± 5.95 h). In vitro cytotoxicity studies of TAM, RES, and their combination (TAM-RES) were evaluated with MCF7 cells. The combination showed significantly lower IC50 compared to TAM with increasing ratio of RES which is a result of apoptosis. HME-based simultaneous extrusion of TAM and RES formulation provides a suitable formulation strategy for breast cancer treatment and establishes proof of concept for extruding multiple drugs simultaneously for other applications in future.