Novel pH-responsive and mucoadhesive chitosan-based nanoparticles for oral delivery of low molecular weight heparin with enhanced bioavailability and anticoagulant effect

Abstract

Low molecular weight heparin (LMWH) shows great anticoagulant effect for prevention and treatment of deep venous thrombosis. However, its oral administration is seriously hindered by multiple obstacles. In this study, a pH-responsive delivery system was developed to protect LMWH from gastrointestinal tract degradation and facilitate its absorption across gastrointestinal mucosa. The LMWH-loaded nanoparticles (pH-TCS/O-CMCS@LMWH) were prepared by ionic-crosslinking reaction between positive-charged amino groups of thiolated chitosan (TCS) as well as o-carboxymethyl chitosan (O-CMCS) and oppositely charged HP55. As a result, the prepared nanoparticles proved to spherical shape with an average size of 332 nm, high encapsulation efficiency of 96.6% and drug-loading content of 12.04 IU/mg. The proposed pH-TCS/O-CMCS@LMWH also showed good colloidal stability, potential mucoadhesive effect and desirable pH-responsive drug release behavior, which decreased pre-mature LMWH release in acidic environment but increase its targeted release in intestine environment. After oral administration, the pH-TCS/O-CMCS@LMWH shown enhanced bioavailability and significant antithrombotic effect in a rat model of venous thrombosis. In conclusion, pH-TCS/O-CMCS nanoparticles can be successfully hold great promising for oral administration of LMWH and potential treatment for thrombosis.