Cubosomes with surface cross-linked chitosan exhibit sustained release and bioavailability enhancement for vinpocetine

Abstract

The present study aims to develop cubosomes with surface cross-linked chitosan for sustained drug delivery and enhanced oral bioavailability of vinpocetine (VPT). GMO based liquid cubosomes with VPT loading were prepared by the high pressure homogenization method. In order to enhance the anti-digestion effect, chitosan was cross-linked on cubosomes by the Schiff reaction, followed by solidification via spray drying. The obtained spray-dried cubosomes (chito-cubosomes) are spherical microspheres with nano-sized holes on the surface. After reconstitution, the particle size and zeta potential of chito-cubosomes were determined to be ∼250 nm and +35.9 mV, respectively. In comparison to unmodified liquid cubosomes, chito-cubosomes exhibited a significant anti-digestion effect with a typical sustained release profile. In comparison to a VPT suspension, liquid cubosomes showed a 2.5-fold higher C _max and 3.0-fold higher AUC_0-∞, while chito-cubosomes further enhanced bioavailability (5.0-fold) with prolonged MRT (2.2-fold) and delayed T _max (2.8-fold). The results suggested that chito-cubosomes could be a promising drug carrier for enhancing oral absorption with sustained release behavior.

Fig. 1. Chemical structure of (a) glycerol monooleate (GMO), (b) chitosan (CS) and (c) vinpocetine (VPT).

Fig. 2. Effect of (a) concentration of poloxamer 407 (1000 bar, 3 cycles); (b) homogenization pressure (3 cycles); and (c) number of homogenization cycles (1200 bar) on particle size and polydispersity index (PI) of VPT-loaded liquid cubosomes.

Fig. 3. AFM image of liquid cubosomes.

Fig. 4. TEM of (a) liquid cubosomes, (b) physical mixture of CS solution and liquid cubosomes, and (c) reconstituted chito-cubosomes.

Fig. 5. SEM of spray dried chito-cubosomes.

Fig. 6. Thermogravimetric thermogram of spray dried chito-cubosomes.

Fig. 7. In vitro digestion profiles of liquid cubosomes, physical mixture of CS solution and liquid cubosomes, and chito-cubosomes using 400 μL or 800 μL of glutaraldehyde for cross-linking.

Fig. 8. In vitro release profiles of VPT dialyzed from solution, liquid cubosomes, physical mixture of CS solution and liquid cubosomes, and reconstituted chito-cubosomes.

Fig. 9. Plasma concentration versus time profiles of VPT in rats after single-dose oral administrations of coarse suspension of VPT, liquid cubosomes, and reconstituted chito-cubosomes. Each point represents mean ± S.D. (n = 5).