ABSTRACT
In this study, a novel oral drug delivery system based on linolenic acid-modified chitosan (CS-LA) micelle was developed to improve the oral bioavailability of doxorubicin (DOX), which was proven by its in vivo intestinal absorption in rats. The DOX-loaded CS-LA micelles (CS-LA@DOX) were prepared by the dialysis method. The synthesized micelle material was identified by proton nuclear magnetic resonance spectroscopy (1H-NMR) and Fourier transform infrared spectroscopy (FT-IR). A series of the micelle properties, including particle size distribution, zeta potential, encapsulation efficiency (EE), drug loading (DL), micromorphology, polymorphy, and critical micelle concentration (CMC) were characterized or tested. The in vitro release of micelles was observed by the dialysis method, and the absorption-promoting effect of micelles was investigated by intestinal circulation experiments in rats. The animal welfare and experimental procedures were in accordance with the regulations of the Animal Ethics Committee of Guilin Medical University. The results of 1H-NMR and FT-IR showed that CS and LA were covalently bound via an amide linkage. The DOX encapsulated in the micelle core was in an amorphous state. The as-prepared micelles in the transmission electron microscope (TEM) image showed regular spherical shapes and uniform sizes with a series of excellent characteristics including (119.2 ± 2.1) nm of mean particle size [polymer dispersity index (PDI), 0.190 ± 0.08], +12.1 mV of zeta potential, (70.23 ± 0.74) % of EE, (8.77 ± 0.02) % of DL and 51.75 μg·mL-1 of CMC. Compared with the reference, DOX hydrochloride, the proposed micelle drug delivery system showed an obvious sustained-release effect in vitro release; and enhanced drug absorption in the small intestine of rats.
ABSTRACT
OBJECTIVE: To investigate the intestinal absorption behaviors of three main active components, liensinine, isoliensinine and neferine in Plumula Nelumbinis extracts in intestine of rats. METHODS: With phenol red as the indicator, in situ single pass intestinal perfusion (SPIP) model was used and the concentrations of the alkaloids in perfusion solution in different intestinal segments (duodenum, jejunum, ileum, and colon) were determined by HPLC. RESULTS: Liensinine, isoliensinine and neferine were absorbed in whole intestinal segments with saturation phenomena. The absorption rate constant (Ka) and/or effective permeability values (Peff) of the three alkaloids mostly had significant difference (P<0.05) at middle and high concentrations of perfusion solution vs those at low concentrations. Liensinine, isoliensinine and neferine possessed better absorption in ileum and colon of intestine. The absorption in duodenum and jejunum mostly displayed no significant difference (P≤0.05). In middle concentration group (117.3 μg·mL-1), neferine was absorbed best among the three alkaloids in colon; in other intestinal sections, the Kd and Peff of the three alkaloids were sequenced as follows: neferine ≤ liensinine ≤ isoliensinine. CONCLUSION: The transport mechanism of liensinine, isoliensinine and neferine in vivo may be active transport or facilitated diffusion.