Improving Paclitaxel permeation and anticancer efficacy through Soluplus-based solid dispersion with Piperine.

OBJECTIVE

This study aimed to develop and optimize a Soluplus-based Paclitaxel-Piperine (PTX-PPN) solid dispersion to enhance PTX solubility, intestinal permeation, and anticancer efficacy in metastatic breast cancer cells.

SIGNIFICANCE: PTX suffers from extremely poor aqueous solubility and dose-limiting toxicity associated with Cremophor® EL-based formulations. PPN is a well-documented bioenhancer and P-glycoprotein inhibitor that may modulate PTX permeation and cytotoxicity.

METHODS

PTX-PPN solid dispersions were prepared via freeze-drying using different PTX-PPN-Soluplus ratios (1:1:1, 1:1:1.5, and 1:1:2 w/w). The formulations were evaluated for drug content, saturation solubility, dissolution and solid-state characterization (FTIR, DSC, XRD, and microscopy). Intestinal permeation was assessed using an ex vivo model of intestinal permeation. Cytotoxicity and apoptosis were evaluated in 4T1 metastatic breast cancer cells.

RESULTS

The optimized PTX-PPN-Soluplus (1:1:1.5) formulation significantly enhanced solubility (PTX: 413.7 ± 36.7 µg/mL; PPN: 827.7 ± 38.7 µg/mL) compared to pure drugs. Solid-state analyses supported the conversion of pure PTX and PPN into an amorphous form. The incorporation of PPN into the PTX-Soluplus formulation significantly improved PTX permeation, resulting in 6-fold enhancement in flux compared with PTX alone. In 4T1 metastatic breast cancer cells, the co-loaded PTX-PPN-Soluplus solid dispersion (16 µM) displayed significantly higher cytotoxicity than PTX alone, reducing cell viability by 1.6-fold. Moreover, the PTX-PPN-Soluplus formulation induced apoptosis almost threefold higher than PTX-PPN alone.

CONCLUSION

The developed PTX-PPN-Soluplus solid dispersion system represents a promising strategy to overcome PTX solubility limitations and support its broader clinical application in breast cancer therapy.