Co-extrusion as manufacturing technique for fixed-dose combination mini-matrices

Abstract

The aim of this study was to develop a multilayer (core/coat) dosage form via co-extrusion, the core providing sustained drug release and the coat immediate drug release. In this study polymers were selected which can be combined in a co-extruded dosage form. Several thermoplastic polymers were hot-melt extruded and evaluated for processability and macroscopic properties (surface smoothness, die swell). Metoprolol tartrate (MPT) and hydrochlorothiazide (HCT) were incorporated as sustained and immediate release model drugs, respectively. Based on the polymer screening experiments a combination of polycaprolactone (core) and polyethylene oxide (coat) was selected for co-extrusion trials, taking into account their drug release profiles and extrusion temperature (70°C). This combination (containing 10% HCT in the coat and 45% MPT in the core) was successfully co-extruded (diameter core: 3mm/thickness coat: 0.5mm). Adhesion between the two polymer layers was good. HCT release from the coat was complete within 30min, while MPT release was sustained over 24h (55%, 70%, 85% and 100% after 4, 8, 12 and 24h, respectively). DSC, XRD and Raman spectroscopy revealed that MPT remained crystalline during extrusion, whereas HCT was dissolved in the polyethylene oxide matrix. The in vivo study revealed no significant differences between the experimental formulation and the reference formulation (Zok-Zid® tablet). Fixed-dose combination mini-tablets with good in vitro and in vivo performance were successfully developed by means of co-extrusion, using a combination of polycaprolactone and polyethylene oxide.