Polymeric Nanoparticles of Enoxaparin as a Delivery System: In Vivo Evaluation in Normal Rats and in a Venous Thrombosis Rat Model

Abstract

Enoxaparin is an anticoagulant widely used in the treatment and prophylaxis of deep vein thrombosis (DVT). The subcutaneous route of administration, sometimes in repeated doses during 24 hours, represents a limitation to its use. Thus, the development of a product that can be administered either subcutaneously, in a smaller number of applications becomes a major challenge, with interesting clinical applications. The use of a system for sustained release of drugs can help to meet that goal, by protecting and enabling a gradual released of the agent. This study consisted of the evaluation of in vivo anticoagulant and antithrombotic activity of biodegradable nanoparticles of poly (ε-caprolactone) (PCL) with enoxaparin after subcutaneous injection. The nanoparticles were prepared by the method of double emulsion (w/o/w) and solvent evaporation. Subcutaneous enoxaparin encapsulated in PCL nanoparticles (1000 IU/kg) showed a sustained release in vivo for up to 12 hours (Cmax 0.62 IU/mL) a significantly longer period (P < 0.01) when compared to free enoxaparin (1000 IU/Kg) that disappeared after 9 hours (Cmax 1.50 IU/mL), however with lower anti-Xa activity. The antithrombotic action of enoxaparin-nanoparticles was tested in a DVT model by stasis in rats. There were virtually no formation of venous thrombosis in any of the rats that received enoxaparin encapsulated in nanoparticles (0.03 mg), with a significant difference when compared to groups that received saline (17.2 mg, P < 0.001) and free enoxaparin (2.87 mg, P = 0.001). In summary, enoxaparin-encapsulated in polymeric nanoparticles showed a sustained release for a greater period than that of enoxaparin, and with excellent antithrombotic action. These results corroborate the promising use of pharmacological nanoparticles in clinical practice.

Characterization of PCL and Chitosan Nanoparticles as Carriers of Enoxaparin and Its Antithrombotic Effect in Animal Models of Venous Thrombosis

“…The preparation of heparin encapsulated in nanoparticles by the double emulsion method water in oil in water (w/o/w) using biodegradable polymers such as PCL and PLGA alone or in combination with other biodegradable polymers (Eudragit RS and RL) has been successfully used. These studies showed reproducible results regarding diameter, encapsulation efficiency, and anti-Xa activity in vitro and in animal models [14][15][16][17].…”

“…We elected this high dose of enoxaparin as encapsulation could compromise the stability, or a sustained and prolonged release could require a higher concentration of the drug. We have previously demonstrated a slow release of encapsulated PCLenoxaparin in vitro during the first 24 hours [17]. The controlled release characteristic of nanomaterials enabling drug liberation for a long period of time and preserving the pharmacological effect without reaching the toxicity range is interesting.…”

The Melding of Nanomedicine in Thrombosis Imaging and Treatment: a Review

“…Recent advances in nanodevices have been largely achieved by either combining older treatment methods with new NP technology, or by implementing entirely novel techniques that have shown significant promise in the field. Nowadays, this ‘branch’ of medicine has been applied, at least at experimental stages with clinical applications for thrombosis [43]. …”

In VivoEvaluation of Complex Biogenic Silver Nanoparticle and Enoxaparin in Wound Healing

“…An example is the topical or parental application of heparin [7][8][9][10][11]. Heparin and enoxaparin (low molecular weight heparin) are used as anticoagulant in the thrombosis treatment [12]. Heparin had been studied to burn treatment in humans and animals showing significant therapeutic results [13,14].…”