Novel lansoprazole-loaded nanoparticles for the treatment of gastric acid secretion-related ulcers: in vitro and in vivo pharmacokinetic pharmacodynamic evaluation

Abstract

The objective of this study is to combine nanoparticle design and enteric coating technique to sustain the delivery of an acid-labile drug, lansoprazole (LPZ), in the treatment of acid reflux disorders. Lansoprazole-loaded Eudragit® RS100 nanoparticles (ERSNP-LPZ) as well as poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PLGANP-LPZ) were prepared using a solvent evaporation/extraction method. The effects of nanoparticle charge and permeation enhancers on lansoprazole uptake was assessed in Caco-2 cells. The confocal microscopic images revealed the successful localization of nanoparticles in the cytoplasm of Caco-2 cells. The cellular uptake of positively charged Eudragit nanoparticles was significantly higher than that of negatively charged PLGA nanoparticles, which were enhanced by sodium caprate via the transcellular pathway. Both types of nanoparticles exhibited sustained drug release behavior in vitro. The oral administration of enteric-coated capsules filled with nanoparticles sustained and prolonged the LPZ concentration up to 24 h in ulcer-induced Wistar rats, and 92.4% and 89.2% of gastric ulcers healed after a 7-day treatment with either EC-ERSNP1010-Na caprate or EC-PLGANP1005-Na caprate, respectively.

Fig. 1

TEM images (50K X) and particle size distributions of ERSNP-LPZ (a and b) and PLGANP-LPZ (c and d)

Fig. 2

Effect of the polymer/drug ratio on a the yield (%), b particle size (nm), c drug loading (%), and d encapsulation efficiency (%) of ERSNP-LPZ. The values represent the mean ± SD (n = 3). Asterisk indicates p < 0.05, and NS indicates p > 0.05 by Student’s t test

Fig. 3

Effect of the polymer/drug ratio on a the yield (%), b particle size (nm), c drug loading (%), and d encapsulation efficiency (%) of PLGANP-LPZ. The values represent the mean ± SD (n = 3). Asterisk indicates p < 0.05, and NS indicates p > 0.05 by Student’s t test

Fig. 4

The LPZ release profiles of white triangle ERSNP1010, white square PLGANP1005, black triangle EC-ERSNP1010, and black square EC-PLGANP1005 in pH 7.4 phosphate-buffered solution. The values represent the mean ± SD (n = 3)

Fig. 5

a Flow cytometry images and b cellular uptake efficiency (%) of a HBSS (control), b coumarin-6, c ERSNP-C6, d PLGANP-C6, e ERSNP-C6-Na caprate, and f PLGANP-C6-Na caprate in Caco-2 cells after a 0.5-h incubation. The values represent the mean ± SD (n = 3). Asterisk indicates p < 0.05, and NS indicates p > 0.05 by Student’s t test

Fig. 6

Confocal microscopy images of Caco-2 cells after incubation with ERSNP-C6, ERSNP-C6-Na caprate, PLGANP-C6, or PLGANP-C6-Na caprate at 37°C for 0.5 h. Green denotes nanoparticles, and red denotes nuclei. XY1, XY2, and XY3 represent images with the FITC filter, RITC filter, and FITC-RITC filter overlay. The green images in YZ projections illustrate the internalized nanoparticles

Fig. 7

The serum LPZ concentration versus time profiles in ulcer-induced Wistar rats after the oral administration of white triangle EC-ERSNP1010, white square EC-PLGANP1005, black triangle EC-ERSNP1010-Na caprate, or black square EC-PLGANP1005-Na caprate (5 mg LPZ/kg). The values represent the mean ± SD (n = 4)

Fig. 8

a Photographs of the stomach opened along the greatest curvature and b the ulcer index values of ulcerated Wistar rats after the oral administration of saline solution (control), EC-ERSNP1010, EC-PLGANP1005, EC-ERSNP1010-Na caprate, EC-PLGANP1005-Na caprate, or RICH® (5 mg LPZ/kg/day) for 7 days. The arrows indicate the ulcerated regions. Asterisk indicates p < 0.05, and NS indicates p > 0.05

Fig. 9

Histopathologic illustrations of healthy tissue and healing ulcer tissues after the oral administration of saline solution (control), RICH® capsule, EC-ERSNP1010, or EC-PLGANP1005 with or without sodium caprate for 7 days. The arrows indicate granulation tissue development during the ulcer healing process (magnification ×100)