VARIOUS WAYS OF MODULATING THE RELEASE OF DILTIAZEM HYDROCHLORIDE FROM HOT-MELT EXTRUDED SUSTAINED-RELEASE PELLETS PREPARED USING POLYMERICMATERIALS

Sustained release pellets were prepared using the continuous process o f hot-melt screw extrusion. Diltiazem hydrochloride was used as a high ly dosed, freely soluble model drug. Pellets obtained with this techni que can be filled into hard gelatin capsules. It was possible to obtai n in vitro release rates low enough to achieve therapeutic plasma leve ls for diltiazem hydrochloride with a once or twice daily administrati on. Firstly, the release profiles from extrudates varying in their pol ymer to drug ratio were analysed using a double exponential decay equa tion in order to discriminate between surface release and diffusion-co ntrolled release phases. Then, to optimize the release profile of the drug the influence of different parameters, such as polymer type, addi tion of pore-forming additives and hydrophilic polymers, or size of th e pellets was studied. With one particular inert polymer, poly(ethylen e-co-vinyl acetate), the possibility of achieving a nearly zero order release without any coating was investigated. Assuming first that this could be achieved by incorporating polymers with pH-dependent behavio ur, the effect of cationic and enteric additives was also evaluated. F inally, swelling agents were included into the pellets, which were abl e to reduce the burst release.