Preparation and evaluation of the doxazosin-bentonite composite as a pH-dependent controlled-release oral formulation

Abstract

Bentonite (BT) is a natural clay mainly composed of montmorillonite which has exchangeable cations in the interlayer space. BT has various advantages as a pharmaceutical excipient for the formulation of drug delivery systems (DDSs), including biocompatibility and unique physicochemical properties (i.e., adsorption and pH -dependent cation exchange). However, previous studies on the application of BT for DDSs were usually limited to the characterization of the in vitro adsorption and release properties. Herein, we prepared and char-acterized a doxazosin-bentonite (DXBT) composite formulation for controlled oral delivery and then evaluated the pharmacokinetics of doxazosin (DX) in rats. The composition of the DXBT composite was optimized based on the adsorption efficiency and the content of DX in the DXBT composite. The change in morphology was observed by scanning electron microscopy (SEM). Intercalation of amorphous DX between the BT interlayer space was confirmed by powder X-ray diffraction (pXRD). The zeta potential of DXBT composite was higher than BT over the pH range between 1 and 8, and was positive in acidic condition and was changed to negative at pH above 4. The DXBT composite showed pH-dependent in vitro release profiles of DX, and the cumulative release amount at 24 h was higher at pH 7.8 than at pH 1.2 and 7.4 (63.9, 29.3 and 47.8%, respectively). In an in vivo pharma-cokinetic study after oral administration in rats, the DXBT composite resulted in a significantly lower peak plasma concentration (Cmax) and longer terminal half-life (t1/2) and mean residence time (MRT) of DX compared to DX solution. Thus, the DXBT composite could be an oral drug delivery platform with pH-dependent controlled -release profiles based on the unique ion-exchange property of BT. <comment>Superscript/Subscript Available</comment