Low molecular weight heparin nanoparticles: mucoadhesion and behaviour in Caco-2 cells

Abstract

Nanoparticles (NPs) have shown their efficiency in increasing the oral bioavailability of macromolecular drugs, among them heparin. However, mechanisms of absorption are still unclear. Here, heparin-loaded NPs were prepared from different polymers (Eudragit ® RS, poly(lactic-co-glycolic acid) (PLGA), and their respective mixtures) and analysed for their mucoadhesive properties using a resonant mirror system. Subsequent binding and drug transport studies of the free heparin and heparin-loaded NPs were carried out on Caco-2 cells. Cationic NPs were found to be mucoadhesive, while pure drug and polyester NPs were not. The adsorption of anionic heparin masked the positive surface charge of the particles, thus partially diminishing the adhesiveness to mucin. Increased binding to Caco-2 cells was found for all NP formulation, with RS/PLGA NPs showing maximum binding. However, the transport of heparin was the same for the RS/PLGA NPs and the PLGA NPs and slightly higher than for the free drug. In all cases, no NP transport across the cell layer was observed. When Caco-2 cells were coated with an additional mucin layer, cell binding of RS NPs and RS/PLGA NPs was further increased. Transport across Caco-2 cells demonstrated similar tendencies to results obtained without mucin. In contrast, cationic NPs led to higher heparin transport in the presence of mucin. The mechanism of drug absorption associated with RS NPs was concluded to be independent of typical transcellular NP transport.

Epithelial Heparin Delivery via Microspheres Mitigates Experimental Colitis in Mice

“…In this context, heparin and its derivates are especially interesting considering their minimal tendency to cross the intact intestinal barrier related to their macromolecular structure. This in turn leads to a very low oral bioavailability in healthy subjects (Hoffart et al, 2006;Lamprecht et al, 2006).…”

Influence of polymers ratio on insulin-loaded nanoparticles based on poly-ε-caprolactone and Eudragit®RS for oral administration

“…Insulin-loaded nanoparticles and/or insulin released from nanoparticles could be taken up by three potential mechanisms: (i) uptake via a paracellular pathway, (ii) transcytosis or receptor-mediated transcytosis and transport via the epithelial cells of the intestinal mucosa, and (iii) lymphatic uptake via the M-cells of the Peyer's patches mostly abundant in the ileum (Damgé et al, 2008). Mucoadhesion of cationic nanoparticles made of Eudragit  RS to mucin layer on Caco-2 cells has already been demonstrated by Lamprecht et al (2006). The mechanism was governed by non-specific particle adhesion to the epithelial barrier followed by a replacement of the drug on the particle surface by mucin.…”

A nanoparticulate drug-delivery system for 20(S)-protopanaxadiol: formulation, characterization, increased oral bioavailability and anti-tumor efficacy

“…The improved oral bioavailability of the PPD nanosuspensions was explained as follows: first, the smaller particle size increased the surface area and reduced the thickness of the diffusion layer of the PPD nanosuspensions against the bulk PPD powder, leading to enhanced PPD dissolution and then enhanced absorption (Hintz & Johnson, 1989;Jia et al, 2002). Second, the adhesion between the nanoparticles and the intestinal villi prolongs the contact of the PPD nanosuspensions with the absorbing membranes of the gut (Lamprecht et al, 2006;. Third, the enhanced bioavailability could also be a result of the nanosuspension existing as amorphous drug compared with the coarse suspension existing as crystalline drug (Andeep et al, 2012).…”