Dual Formulation and Interaction Strategies to Enhance the Oral Bioavailability of Paclitaxel

Abstract

A self-microemulsifying drug delivery system (SMEDDS) was developed to enhance Paclitaxel (PTX) solubility and membrane permeability, thus improve its bioavailability. Pre-formulation studies were performed to optimize PTX-SMEDDS formulation. Then, in vitro characteristics of the formulation were determined and PTX oral absorption was investigated in rabbits. The optimized PTX-SMEDDS showed emulsification time of 31 ± 4 s, droplet size of 19.4 ± 0.5 nm, poly-dispersibility index of 0.35 ± 0.08, percentage transmittance after dilution of 99 ± 0.02%, zeta potential of 36.82 ± 1.8 mv, cloud point of 78 ± 0.5 °C and infinite dilution capability. The formulation maintained its physical and chemical stability during storage at 4 °C for three months. Oral administration of 10 mg/kg of 1.5% w/w PTX-loaded SMEDDS to rabbits increased PTX bioavailability by 4.5 fold in comparison to untreated PTX suspension. While when the rabbits received 1.5% w/w PTX-loaded SMEDDS after pretreated with 1 dose and 2 doses of cyclosporine A, PTX bioavailability increased by 4.4 and 7.8 fold, respectively. This indicates that the combined effect of the SMEDDS formulation in addition to pretreatment with P-gp and CYP3A4 inhibitor, can improve the oral bioavailability of poorly soluble and poorly permeable drugs such as PTX in rabbits.

Keywords: Bioavailability; Cyclosporine A; Drug delivery system; Microemulsion; Oral absorption; Paclitaxel; Preclinical pharmacokinetics; Preformulation; Self-emulsifying; Surfactants.