Polysaccharides-based nanocomplexes for the prolonged delivery of enoxaparin: In-vitro and in-vivo evaluation

Abstract

Thromboprophylaxis and anticoagulant therapy face serious medical challenges in terms of how crucial it is to maintain therapeutic activity of the anticoagulant agent over the required period of time. Failure to do so will lead to an increased risk of clot propagation if a subtherapeutic drug level is reached. On the other hand, higher-than intended anticoagulation levels might lead to an enhanced risk of hemorrhagic complications. Nanocomplexes (NCs) for the controlled delivery of the antithrombotic Enoxaparin (Enox) with dextran sulfate (DS) and chitosan (CS) were formulated, in an attempt to circumvent therapeutic and compliance challenges associated with the prolonged administration of the current dosage form. Using polyelectrolyte complexation method, various fabrication and formulation parameters were tested. Assessment of ex-vivo stability of selected formulae in rat serum was done prior to determination of their pharmacokinetic profile. High EE% was achieved in all systems prepared. In absence of DS, target size was obtained when 0.54mg/mL CS at an initial pH of 5 and Enox to CS mass ratio of 1:2.5 were employed at room temperature. These parameters were shifted to new optima upon introduction of DS. The anticoagulant activity of NCs (in absence/presence of DS) was significantly sustained compared to the market product (135 and >144h versus 5h, respectively).

Keywords: Anticoagulant; Chitosan; Dextran sulfate; Enoxaparin; Nanocomplexes; Sustained release.