Pharmaceutical nanotechnologyAlginate coated chitosan core shell nanoparticles for oral delivery of enoxaparin: In vitro and in vivo assessment
Graphical abstract
Introduction
Low molecular weight heparin (LMWH) is glycosaminoglycan, which is used as anticoagulant agent in the treatment of vascular disorders like venous thromboembolism, deep vein thrombosis and pulmonary embolism. Apart from anticoagulant activity, LMWH has been also found applicable in inhibition of progression of cancer as well as in therapy of rheumatoid arthritis attributed to antiangiogenic activity of LMWH. The advantages of LMWH over heparin are that it does not cause severe toxicities, for example thrombocytopenia and bleeding (Hwang et al., 2012, Khatun et al., 2012, Jain et al., 2013). The clinical applicability of this low molecular weight heparin therapy is limited by the fact that it is given only by parenteral route due to its high molecular size as well as high negative charge, poor permeation through intestinal wall and high water solubility. In order to improve patient compliance oral heparin therapy is needed for long time. Various approaches including penetration enhancers (Hayes et al., 2006), microparticles (Javot et al., 2009), polymeric nanoparticles (Chen et al., 2009) dendrimeric nanocarriers (Bai and Ahsan, 2009), chemical conjugates (Lee et al., 2006), etc. have been investigated for oral delivery of heparin. At present no oral formulation of heparin is available in the market (Kim et al., 2011, Hwang et al., 2012).
Oral formulation offers economical and effective solution to limitations of parenteral administration in addition to improved patient compliance and non-invasive administration (Shah et al., 2005, Oliveira et al., 2012, Paliwal et al., 2012). Chitosan is a biodegradable, biocompatible, mucoadhesive cationic polymer, which can easily form complexes or nanoparticles in aqueous medium with the ability to encapsulate drug molecules. Nanoparticles prepared from chitosan and chitosan derivatives have shown promising potential in oral delivery of bioactives including LMWH owing to their biocompatibility, low toxicity and high loading potential (Wan et al., 2011, Oliveira et al., 2012, Trapani et al., 2013). Oral delivery potential of chitosan is limited by its solubility at acidic pH, which causes dissolution of chitosan at gastric pH condition, leading to loss of mucoadhesive and permeability enhancing properties of chitosan (Li et al., 2008, Paliwal et al., 2012). Sodium alginate has been exploited for sustained, controlled and oral delivery of bioactives without risk of mucosal damage (Kanjanabat and Pongjanyakul, 2011, Rajesh et al., 2012). Sodium alginate coating may be applied to chitosan nanoparticles to protect encapsulated drug from enzymes and acidic environment of gastrointestinal (GI) tract due to acid-resistant property of alginate. Alginate coating may further modify the release behavior of bioactive from chitosan nanoparticles instigating more efficient oral delivery aptitude. The alginate coated chitosan nanoparticles are also easy to prepare under mild conditions like aqueous medium and mild agitation. The alginate–chitosan based nanoparticulate systems have been studied for delivery of various bioactives like hepatitis B surface antigen (Borges et al., 2008), turmeric oil (Lertsutthiwong et al., 2009) and gene transfection (You et al., 2006), etc. Oral delivery with chitosan nanoparticles coated with sodium alginate is expected to provide advantages of improved stability, controlled drug delivery, high drug payload as well as protection from acidic and proteolytic environment of GI tract (Li et al., 2008, Kanjanabat and Pongjanyakul, 2011, Oliveira et al., 2012).
In this study we proposed to evaluate alginate coated chitosan nanoparticles loaded with low molecular weight heparin, enoxaparin, for oral delivery as well as for controlled and prolonged release of enoxaparin for with improved patient compliance.
Section snippets
Materials
Chitosan (molecular weight 150 kDa, degree of deacetylation 85%, purified viscosity grade 80 cps) was received as a benevolent gift from Central Institute of Fisheries Technology (Cochin, India). LMWH, Enoxaparin sodium (mean MW 4.5 kDa) was purchased from Emcure pharmaceuticals (Pune, India). Sodium alginate (medium viscosity grade ∼50 kD) and dialysis membrane (MWCO 12–14 kDa) were purchased from Himedia Labs, Mumbai, India. Sodium tripolyphosphate (STPP) was purchased from Sigma (Germany). Other
Preparation of core shell nanoparticles
The chitosan nanoparticles were prepared by ionic gelation technique using different chitosan: STPP ratio and optimized on the basis of particle size and drug entrapment efficiency (Table 1). The size of nanoparticles was found to increase from 177 ± 4.2 to 289 ± 5.4 nm on increasing the ratio of polymer from 2 to 6 with respect of STPP. This increase in size was possibly attributed to increased collision of the chitosan polymer with TPP ions. Chitosan: STPP ratio 5:1 was considered optimum because
Discussion
Oral delivery of therapeutic heparins is foremost requirement for non-invasive and non-hospitalized treatment of vascular disorders (deep vein thrombosis, pulmonary embolism and venous thromboembolism). This urge necessitated the development of a macromolecular carrier system with optimum hydrophilicity, high charge density to interact with intestinal epithelium and traverse across the intestinal barrier (Goldberg and Gomez-Orellana, 2003, Paliwal et al., 2011, Hwang et al., 2012). The
Conclusion
The strategy for the oral delivery of low molecular weight heparin is desperately needed. Chitosan nanoparticles presented excellent opportunity in this regard but it suffers with some problems including lower solubility of chitosan at neutral or at higher pH. So development of core shell nanoparticles by coating chitosan nanoparticles with alginate may overcome the limitations of plain chitosan nanoparticles. The study suggest that alginate coated chitosan core shell nanoparticles could be
Acknowledgement
Author Archana Pataskar is grateful to All India Council for Technical Education (AICTE), New Delhi, India for providing Junior Research Fellowship (JRF).
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