Biodegradable nanoparticles as a potential oral delivery system for oestradiol: pharmacokinetic and pharmacodynamic evaluations

The present dissertation was aimed at realizing the therapeutic potential of oestradiol by oral dosing aided by a nanoparticulate delivery system with a view to improving the bioavailability and minimizing the possible toxic effects of oestradiol. The most widely used polyester; poly(lactide-coglycolide) (PLGA) was chosen to develop oestradiol entrapped nanoparticles by the emulsion-diffusion-evaporation method. The nanoparticles were in the size range of 100-150 nm and ideal for oral dosing. A detailed pharmacokinetic study of oestradiol as a function of dose and nanoparticle characteristics was carried out in rats, which demonstrated improved bioavailability and sustained release of oestradiol with the nanoparticulate formulations. These polymeric nanoparticles (given once in 3 days against daily administration of suspension) were subsequently evaluated in the ovariectomized (OVX) rat model of hyperlipidaemia, where they were found effective in treating post-menopausal hyperlipidaemia at a dose 3 times less than simple oral drug suspension. Further, attempts were also made to improve brain delivery of oestradiol by oral administration aided by Tween 80 (T-80) coated nanoparticles. The process of T-80 coating on the nanoparticles was optimized and the pharmacokinetics of oestradiol nanoparticles was studied as a function of T-80 coating. In vitro data in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) confirmed the stability of T-80 coating and the amount of the T-80 remaining on the surface was proportional to the initial coating concentration. Nanoparticles coated with 4% T-80 showed significantly higher brain oestradiol levels as compared to uncoated ones. Finally, these surface coated oestradiol nanoparticles were evaluated in the OVX rat model of Alzheimer’s disease (AD) and were successful in preventing the expression of amyloid beta-42 (Aβ42) immunoreactivity in hippocampus. Together, the data indicates that nanoparticles can be tailored appropriately to achieve different target tissue drug levels that are not possible by conventional means, which can make the treatment/prevention of a variety of diseases possible.