Glutaraldehyde-crosslinked chitosan-polyethylene oxide nanofibers as a potential gastroretentive delivery system of nizatidine for augmented gastroprotective activity

Abstract

Nizatidine (NIZ), a histamine H 2 -receptor antagonist, is soluble and stable in the stomach, however, it exhibits a short half-life and a rapid clearance. Therefore, chitosan (CS) and polyethylene oxide (PEO) nanofibers (NFs) at different weight ratios were prepared by electrospinning and characterized. The selected uncrosslinked and glutaraldehyde-crosslinked NFs were investigated regarding floating, solid-state characteristics, in vitro release, and in vitro cytotoxicity. The cytoprotective activity against ethanol-induced gastric injury in rats was evaluated through macroscopical, histopathological, immunohistochemical, and oxidative stress examinations. NFs based on 8:2 CS:PEO exhibited the smallest diameter (119.17 ± 22.05 nm) and the greatest mucoadhesion (22.82 ± 3.21 g/cm 2 ), so they were crosslinked with glutaraldehyde. Solid-state characterization indicated polymers interaction, a successful crosslinking, and NIZ dispersion in NFs. Crosslinking maintained swollen mats at pH 1.2 (swelling% = 29.47 ± 3.50% at 24 h), retarded their erosion at pH 6.8 (swelling%= 84.64 ± 4.91% vs. 25.40 ± 0.79% for the uncrosslinked NFs at 24 h), augmented the floating up to 24 h vs. 10 min for the uncrosslinked NFs at pH 1.2 and prolonged the drug release (%drug released ≥ 93% at 24 h vs. 4 and 5 h for the uncrosslinked NFs at pHs 1.2 and 6.8, respectively). The viability of Caco-2 cells ≥ 86.87 ± 6.86% revealed NFs biocompatibility and unreacted glutaraldehyde removal. Crosslinking of 8:2 CS:PEO NFs potentiated the antiulcer activity (38.98 vs. 8.67 for the uncrosslinked NFs) as well as it preserved the gastric wall architecture, COX-2 expression, and oxidative stress markers levels of the normal rats.

Mucus interaction to improve gastrointestinal retention and pharmacokinetics of orally administered nano-drug delivery systems

“…Cheng et al [ 131 ] used chitosan-coated nanoparticles for insulin delivery and found that they exhibited a 16-fold increase in insulin AUC when compared to an oral solution, and roughly 80% of that of a subcutaneous injection of insulin. Abd El Hady et al [ 132 ] synthesized chitosan–polyethylene oxide nanofibers for nizatidine delivery and found that nanofibers with an 8:2 ratio of chitosan to polyethylene oxide showed the highest mucoadhesive strength (22.82 g/cm 2 ), as well as prolonged drug release when compared to control nanofibers.…”

Gastroretentive Technologies in Tandem with Controlled-Release Strategies: A Potent Answer to Oral Drug Bioavailability and Patient Compliance Implications

“…The potential of cross-linked chitosan and PEO combinations in nanofibre preparation was also reported by Abd El Haby et al who, apart from in vitro and ex vivo characterisation, conducted an in vivo study in rats for the prepared nanofibres. The results demonstrated a robust gastroprotective activity of nizatidine that was significantly more potent when formulated in cross-linked nanofibres, compared to drug solution and uncross-linked nanofibres [209].…”

Advanced 3D Electrospinning “Xspin” System: Fabrication of Bifiber Floating Oral Pharmaceutical Scaffolds for Controlled Drug Delivery

“…Then, the Petri dish was kept at 37 °C using a hot air incubator (IVYX Scientific 5L Incubator, USA). The swelling behavior was observed at predetermined time intervals: 15, 30, 45, 60, 75, 90, 105, 120 min, and 24 h. At each time, samples were removed carefully from the Petri dish and blotted off cautiously on tissue papers to remove the surface-adhered liquid droplets and reweighed to constant weight . The experiment was done in triplicate, and the mean values were calculated.…”

“…In Vitro Floating (Buoyancy) Test. In vitro floating and buoyancy studies were carried out for all selected four nanofibrous mats based on the technique explained by Abd El Hady et al 29 Nanofibrous mats (1 × 1 cm 2 ) were placed in a flask containing 100 mL of 0.1 N HCl (pH 1.2) at 37 °C. The time necessary for test samples to go from the bottom to the surface of dissolution medium was called floating lag time (FLT).…”