Oral and parenteral formulations of docetaxel based on sustained release lipid nanoparticles

Abstract

The aim of this study is to investigate physicochemical properties, stability, in vitro antitumor effect and oral bioavailability of docetaxel (DTX)-loaded lipid nanoparticles (NPs) prepared by hot nanoemulsion-based technique using palmityl alcohol as a solid lipid and Tween 40/Span 40/Myrj S40 as surfactants mixture. DTX-loaded NPs were spontaneously prepared after cooling hot nanoemulsions. The physicochemical properties of DTX-loaded NPs were characterized in terms of particle size, polydispersity index, zeta potential, incorporation efficiency, TEM, DSC and PXRD. DTX-loaded NPs had the particle size of 89.1 ± 1.7 nm and polydispersity index of 0.121 ± 0.021 with incorporation efficiency of 96.6 ± 2.3%. From the TEM images, DTX-loaded NPs were found uniform and spherical in shape. The results of PXRD and DSC confirmed that DTX was incorporated well in the solid lipid core and exists in an amorphous state. From stability tests, DTX-loaded NPs were stable at 4°C for 180 days. For application of DTX-loaded NPs to oral delivery, in vitro release of DTX from NPs was studied in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 6.8) using a dialysis bag method. DTX-loaded NPs slowly released 80% of DTX in simulated gastric fluid (pH 1.2) and 95% of DTX in simulated intestinal fluid (pH 6.8) for 72 h, while commercial micelle formulation released most of DTX within 12 h in both fluids. Pharmacokinetic study was performed after oral administration of DTX-loaded NPs in rats at the dose of 10 mg/kg. AUC and Cmax of DTX increased 3.7- and 1.3-fold, respectively, compared with DTX micelle formulation. For parenteral delivery, in vitro release of DTX from NPs was studied in PBS (pH 7.4). DTX-loaded NPs slowly released 90% for DTX for 72 h. In vitro anticancer activity against MCF-7 was assessed by MTT assay. IC50 values of DTX-loaded NPs, DTX micelle formulation and DTX solution against MCF-7 cell were 2.50 ± 0.14 and 4.81 ± 0.15, respectively. These results indicate that DTX-loaded NPs had an enhanced in vitro anticancer activity against MCF-7 cell compared with DTX micelle formulation. Pharmacokinetic study was performed after intravenous administration of DTX-loaded NPs in rats at the dose of 5 mg/kg. AUC and half life of DTX from NPs formulation increased 2.8- and 4.4-fold, respectively, as compared to DTX micelle formulation. In conclusion, DTX-loaded NPs prepared by hot nanoemulsion-based technique showed a sustained-release property, improved oral bioavailability and prolonged retention in systemic circulation.