pH-responsive thiolated chitosan nanoparticles for oral low-molecular weight heparin delivery: in vitro and in vivo evaluation

Abstract

The aim of present study was to investigate a pH-responsive and mucoadhesive nanoparticle system for oral bioavailability enhancement of low-molecular weight heparin (LMWH). The thioglycolic acid (TGA) was first covalently attached to chitosan (CS) with 396.97 ± 54.54 μmol thiol groups per gram of polymer and then the nanoparticles were prepared with thiolated chitosan (TCS) and pH-sensitive polymer hydroxypropyl methylcellulose phthalate (HPMCP) by ionic cross-linking method. The obtained nanoparticles were characterized for the shape, particle size, zeta potential, drug entrapment efficiency and loading capacity. In vitro results revealed the acid stability of pH-responsive nanoparticles, which had a significant control over LMWH release and could effectively protect entrapped drugs in simulated gastric conditions. By the attachment of the thiol ligand, an improvement of permeation-enhancing effect on freshly excised carp intestine (1.86-fold improvement) could be found. The mucoadhesive properties were evaluated using fluorescently labeled TCS or CS nanoparticles. As compared with the controls, a significant improvement of mucoadhesion on rat intestinal mucosa was observed in TCS/HPMCP nanoparticles via confocal laser scanning microscopy. The activated partial thromboplastin time (APTT) was significantly prolonged and an increase in the oral bioavailability of LMWH was turned out to be pronounced after oral delivered LMWH-loaded TCS/HPMCP nanoparticles in rats, which suggested enhanced anticoagulant effects and improved absorption of LMWH. In conclusion, pH-responsive TCS/HPMCP nanoparticles hold promise for oral delivery of LMWH.

Micro/nanofabricated platforms for oral drug delivery

“…Among these materials, chitosan has been highly utilized in a number of oral drug delivery systems, including chitosan-based micro- and nanoparticulate drug delivery systems [89–94], chitosan-drug conjugates [95, 96], and chitosan macroscale patches [97, 98]. Chitosan is an attractive material for micro/nanofabricated platforms as it is compatible with a number of microfabrication approaches [99, 100], is stable through pH values relevant to GI physiology [101], and has been utilized in microfabricated oral drug delivery systems [58, 102].…”

Non-Biological Complex Drugs

“…This seems to be quite a challenging task, but some attempts are being made in that direction (Martínez-González and Rodríguez 2010). A recent study in rats has shown promising results with the use of nanoparticles prepared with thiolated chitosan and the pH-sensitive polymer hydroxypropyl methylcellulose phthalate (HPMCP) by an ionic cross-linking method (Fan et al 2014). Oral formulations are also being developed for low molecular weight heparin derivatives with anti-angiogenic properties potentially applicable to cancer patients, by chemical conjugation with tetrameric deoxycholic acid and physical complexation with deoxycholylethylamine (Alam et al 2014).…”

Low molecular weight heparins for current and future uses: approaches for micro- and nano-particulate delivery

“…In another attempt, enoxaparin-loaded NPs possessing both pH-responsive and mucoadhesive properties were formulated using hydroxy propyl methyl cellulose phthalate (HPMCP) as an enteric coating material and thiolated chitosan as mucoadhesive polymer (Fan et al, 2014). A pronounced improvement of oral BAV, which reached 21% was reported holding promise for these systems as potential carriers for oral delivery of LMWHs.…”

“…Moreover, LMWHs have been used for maintenance of vessel patency during hemodialysis and artery bypass grafting (Patel et al, 2009), prevention of acute bronchoconstrictor responses and airway hyper-responsiveness in asthma (Campo et al, 1999;Ahmed et al, 2000) and regulation of growth factor activity in various vascular disorders and angiogenesis (Reyes-Ortega et al, 2013). Nevertheless, their high anionic charge density, large molecular weight and low stability in acidic stomach pH limit their gastrointestinal absorption, as well as, absorption from other non-invasive routes (Bai et al, 2007;Scala-Bertola et al, 2009;Fan et al, 2014;Hwang & Byun, 2014) rendering the parenteral route the most efficient delivery way so far. However, the need for daily subcutaneous injections (SC) limits its outpatient use (Baldwin et al, 2014).…”

“…Quantification of the LMWHs released from gels into skin and plasma samples proved the applicability of the use of gels based on NPs for topical delivery of LMWHs with minimal systemic side effects. In their search for optimum formulations, beside the routine characterization of the developed delivery platforms, various techniques had been used to understand cellular uptake, fate of nanomaterials and mechanisms of enhancement of bioavailability achieved (Bagre et al, 2013;Fan et al, 2014).…”