Development and in vivo evaluation of nanoemulsions for oral delivery of low molecular weight heparin

Aim: The aim of this study was the development and in vivo evaluation of different types of nanoemulsions for oral delivery of low molecular weight heparin (LMWH). Methods: Nanoemulsions (NE) were developed consisting of mainly non-digestible components and variations of polyglycerol-, PEGylated or zwitterionic surfactants. To incorporate LMWH in the oily droplets, hydrophobic ion pairs were formed with several cationic surfactants. Loaded and unloaded NE were evaluated for their size, zeta potential, stability towards pancreatin, hemolytic and toxic properties. Finally, an in vivo study on oral LMWH delivery was performed. Results: Droplet size of all formulations was below 150 nm with a PDI <0.4. Highest logK1-butanol/water was obtained for the complex of LMWH and didecyldimethylammonium bromide (HIP). This complex was incorporated into NE containing polyglyceroland PEGylated surfactants up to a concentration of 5% (m/v) and in zwitterionic NE up to 10% (m/m). NE containing polyglycerol-surfactants were digested to a higher extent than NE containing PEGylated surfactants. The zwitterionic NE without glycerides did not show any lipolysis but the zwitterionic NE which contained high amounts of glycerides was rapidly degradable. NE with polyglycerolsurfactants were less toxic and hemolytic than NE with PEGylated surfactants and zwitterionic NE. Toxic potential increased with HIP-loaded formulations. When performing in vivo studies, oral bioavailability of LMWH was increased up to 2.6% with non-digestible NE. Conclusion: According to these results, non-digestible nanoemulsions improve oral bioavailability of LMWH more efficiently than biodegradable formulations.