Novel Mucoadhesive Chitosomes as a Platform for Enhanced Oral Bioavailability of Cinnarizine

Abstract

Purpose: Cinnarizine (CIN) is a class II BSC drug, suffering from erratic bioavailability due to its pH-dependent solubility. It has preferential absorption in the stomach. In this study, new chitosan (CS) coated niosomes of CIN (CIN-loaded chitosomes) have been developed to extend the gastric retention and ameliorate CIN oral bioavailability.

Methods: Various CIN-loaded niosomes were fabricated by thin-film hydration technique and fully characterized. Based on the predetermined criteria of low particle size (PS) and high entrapment efficiency percent (EE%), niosomal formulation F1 was selected and further coated with different CS concentrations. The optimized chitosomal formulation (C2) was evaluated through solid state characterization and mucoadhesive efficiency testing. It was also subjected to cytotoxicity study on Caco-2 cells; besides, in vitro drug release, stability and pharmacokinetic studies were assessed.

Results: The optimized chitosomal formulation (C2) exhibited an EE% of 58.30±2.75%, PS of 440 ±13.03 nm, PDI of 0.335±0.21 and ZP of +28.1±0.10 mv. Solid state characterization results revealed the compatibility between the vesicle components and the entrapment of CIN within niosomal vesicles. C2 formulation demonstrated favorable mucoadhesive efficiency. The cytotoxicity study on Caco-2 cells manifested the safety of the optimized chitosomal formulation (C2) over the free drug. Additionally, it displayed a remarkable sustaining of CIN in vitro release up to 8 h and exhibited a good stability at the refrigerated temperature up to 3 months. In vivo pharmacokinetic assessment revealed that the CIN bioavailability from the optimized chitosomal formulation C2 was enhanced by 2.79 and 1.92 folds compared to the free drug and uncoated niosomal formulation F1, respectively. The priority of the chitosomal formulation (C2) over the niosomal one (F1) was also conferred.

Conclusion: Novel formulation of chitosan coated niosomes (chitosomes) could be presented as a promising platform to improve the oral bioavailability of drugs with narrow absorption window.

Keywords: chitosan; cinnarizine; mucoadhesion; niosome.

Figure 1

Chemical structure of CIN.

Figure 2

Size distribution curve of niosomal formulation F1 (A), size distribution curve of chitosomal formulation C2 (B), ZP curve of niosomal formulation F1 (C) and ZP curve of chitosomal formulation C2 (D).

Figure 3

TEM images of niosomal formulation F1 (A) and chitosomal formulation C2 (B).

Figure 4

SEM image of the freeze-dried niosomal formulation F1 (A) and chitosomal formulation C2 (B).

Figure 5

FTIR spectra of CIN (I), CH (II), Span 60 (III), CS (IV), physical mixture (V), lyophilized plain C2 formulation (VI) and lyophilized CIN-loaded C2 formulation (VII).

Figure 6

DSC thermograms of CIN (I), CH (II), Span 60 (III), CS (IV), physical mixture (V), lyophilized plain C2 formulation (VI) and lyophilized CIN-loaded C2 formulation (VII).

Figure 7

XRP diffractograms CIN (I), CH (II), Span 60 (III), CS (IV), physical mixture (V), lyophilized plain C2 formulation (VI) and lyophilized CIN-loaded C2 formulation (VII).

Figure 8

Mucoadhesive efficiency of niosomal formulation (F1) and chitosomal formulation (C2).

Figure 9

Cell viability of Caco-2 cells incubated with free CIN, chitosomal formulation C2 and its corresponding plain one for 24 h.

Figure 10

In vitro release pattern of free CIN, niosomal formulation (F1) and chitosomal formulation (C2).

Figure 11

Plasma concentration–time curve after oral administration of free CIN, niosomal formulation (F1) and chitosomal formulation (C2) to male Sprague Dawley rats.

Figure 12

In vitro-in vivo correlation of the optimized chitosomal formulation (C2).