Chitosan based polymer-lipid hybrid nanoparticles for oral delivery of enoxaparin

Abstract

In the present study, chitosan based polymer-lipid hybrid nanoparticles (PLNs) were prepared by a self-assembly method and their use as the carrier for oral absorption enhancement of enoxaparin was evaluated. The enoxaparin-loaded nanoparticles were composed of chitosan as the polymer and glyceryl monooleate as the lipid with a lipid/polymer mass ratio ranging from 0 to 0.3, and F127 was added as a stabilizer. It was found that the PLNs showed a higher surface hydrophobicity but mucoadhesive properties similar to those of chitosan based nanocomplexes. Results from DSC experiments and NMR solvent relaxation study indicate that glyceryl monooleate was completely incorporated into the nanoparticles and the lipid/polymer ratio affected the extent of lipid-polymer interaction inside the nanoparticles and the resultant internal structures. The stability of the PLNs in simulated gastrointestinal fluids was also affected by the lipid/polymer ratio; the best stability was shown by nanoparticles with a lipid/polymer ratio of 0.2. Nanoparticles with the optimal composition significantly enhanced the oral bioavailability of enoxaparin with a 4.5-fold increase in AUC in comparison with a solution of enoxaparin. In conclusion, GMO/CS based PLNs can provide a new insight to develop orally applicable delivery system for hydrophilic macromolecules. Their absorption can be enhanced with proposed PLNs and preparation of this PLNs was also found to be easy comparing to other similar methods.

Introduction

Low molecular weight heparin (LMWH) is a well-established, clinically used anticoagulant for the treatment of vascular disorders like venous thromboembolism, deep vein thrombosis, and pulmonary embolism (Arbit et al., 2006). At present, LMWH can only be administrated by parenteral routes for clinical applications. Although oral administration of LMWH is more desirable with respective to patient compliance, the oral absorption of LMWH is extremely poor due to its high molecular size, dense negative charge, high water solubility, poor permeation through intestinal wall, and first-pass effect (Goldberg and Gomez-Orellana, 2003). Various approaches have been explored to enhance the oral absorption of LMWH, including co-administration with penetration enhancers (Hayes et al., 2006), the use of microparticles (Lanke et al., 2009), nanoparticles (Hallan et al., 2017), and lipid-drug conjugates (Paliwal et al., 2011). An approach involving the hydrophobic modification of LMWH was reported to be an effective strategy to enhance the oral absorption of LMWH. A significantly higher bioavailability (p < 0.05) was shown by using solid lipid nanoparticles (SLNs) loaded with LMWH-saturated fatty acids conjugates in comparison with the results achieved by unmodified LMWH loaded SLNs (Paliwal et al., 2011). However, the activity of LMWH may be reduced after the drug-lipid conjugate formation. Our previous study demonstrated that hydrophobic modification of chitosan enhanced the oral absorption of LMWH significantly as compared to unmodified chitosan based systems (Wang et al., 2014). However, hydrophobic modification of the polymer carrier via a chemical synthetic reaction is complex and difficult to control, hence it is highly desirable to search for other novel hydrophobic modification methods that are less complex and more reproducible.

Recently, a self-assembly physical method was devised for the preparation of polymer-lipid hybrid nanoparticles (PLNs) which possess the desirable characteristics of both a polymeric carrier and a lipid carrier (Raemdonck et al., 2014). By the appropriate selection of lipids and polymers, the physicochemical properties of the hybrid nanoparticles can be optimized to address several drug delivery challenges associated with nanoparticles. For example, improved stability (Jc Bose et al., 2016), controllable drug release characteristics (Hallan et al., 2017, Hu et al., 2015) and triggered drug release (Yao et al., 2017) have been achieved by hybrid nanoparticles developed by a rational design.

In the present study, chitosan (CS) was selected as the polymer based on its cationic charge, mucosal adhesion, and capacity to open tight junctions reversibly (Yang et al., 2014), glyceryl monooleate (GMO) was selected as the lipid, and enoxaparin (ENO) is selected as the drug model. Polymer-lipid hybrid nanoparticles (PLNs) were prepared by a self-assembly process coupled with an ultrasonic treatment. Physicochemical properties of the hybrid nanoparticles were characterized with respective to their particle size, zeta potential, drug encapsulation efficiency, and morphology. Furthermore, the influence of GMO/CS ratio on the surface hydrophobicity, mucoadhesive properties, microstructures, stability in simulated gastrointestinal fluids, and in vivo drug absorption of the hybrid nanoparticles were investigated using CS based nanocomplexes for comparison.