Novel self assembling nanoparticles for the oral administration of fondaparinux: Synthesis, characterization and in vivo evaluation

• Published in: Journal of controlled release 2014-11, Vol.194, p.323-331
• Main Authors: Ralay-Ranaivo, Bettina, Desmaële, Didier, Bianchini, Elsa P., Lepeltier, Elise, Bourgaux, Claudie, Borgel, Delphine, Pouget, Thierry, Tranchant, Jean François, Couvreur, Patrick, Gref, Ruxandra
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anticoagulants - administration & dosage; Anticoagulants - pharmacokinetics; Anticoagulants - pharmacology; Blood Coagulation - drug effects; Cationic squalenyl derivative; Dose-Response Relationship, Drug; Drug Carriers; Drug Compounding; Drug Stability; Fibrinolytic Agents - administration & dosage; Fibrinolytic Agents - pharmacokinetics; Fibrinolytic Agents - pharmacology; Fondaparinux; Injections, Intravenous; Male; Nanoparticle; Nanoparticles; Particle Size; Polysaccharides - administration & dosage; Polysaccharides - pharmacokinetics; Polysaccharides - pharmacology; Rats; Rats, Sprague-Dawley; Self-assembly; Squalene - analogs & derivatives; Squalene - chemistry
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2014.07.060

Fondaparinux (Fpx) is the anticoagulant of choice in the treatment of short- and medium-term thromboembolic disease. To overcome the low oral bioavailability of Fpx, a new nanoparticulate carrier has been developed. The nanoparticles (NPs) contain squalenyl derivatives, known for their excellent oral bioavailability. They spontaneously self-assemble upon both electrostatic and hydrophobic interactions between the polyanionic Fpx and cationic squalenyl (CSq) derivatives. The preparation conditions were optimized to obtain monodisperse, stable NPs with a mean diameter in the range of 150–200nm. The encapsulation efficiencies were around 80%. Fpx loadings reached 39wt.%. According to structural and morphological analysis, Fpx and CSq organized in spherical multilamellar (“onion-type”) nanoparticles. Furthermore, in vivo studies in rats suggested that Fpx was well absorbed from the orally administered NPs, which totally dissociated when reaching the blood stream, leading to the release of free Fpx. The Fpx:CSq NPs improved the plasmatic concentration of Fpx in a dose-dependent manner. However, the oral bioavailability of these new NPs remained low (around 0.3%) but of note, the Cmax obtained after oral administration of 50mg/kg NPs was close to the prophylactic plasma concentration needed to treat venous thromboembolism. Moreover, the oral bioavailability of Fpx could be dramatically increased up to 9% by including the nanoparticles into gastroresistant capsules. This study opens up new perspectives for the oral administration of Fpx and paves the way towards elaborating squalene-based NPs which self assemble without the need of covalently grafting the drug to Sq. [Display omitted]