How to easily provide zero order release of freely soluble drugs from coated pellets.

ABSTRACT

Coated pellets offer a great potential as controlled drug delivery systems. However, constant drug release rates are difficult to achieve with this type of dosage forms if the drug is freely water-soluble. This is because diffusional mass transport generally plays a major role and with time the drug concentration within the system decreases, resulting in decreased concentration gradients, which are the driving forces for drug release. Thus, generally "curve-shaped" release profiles with monotonically decreasing slopes are observed. This type of release kinetics might be inappropriate for an efficient and safe drug treatment. Despite the great practical importance of this potentially crucial formulation challenge, surprisingly little is yet known on how to effectively address it. In this study, a novel approach is presented based on sequential layers of drug and polymer (initially free of drug) to provide a non-homogeneous initial drug distribution, combined with lag-time effects, and partial initial drug diffusion towards the pellet's core. Sugar and microcrystalline cellulose beads were used as starter cores, metoprolol succinate as freely soluble drug, ethylcellulose, and poly(vinyl acetate) as release rate controlling polymers. The type, number, thickness, and sequence of the drug and polymer layers were varied. Interestingly, a rather simple four layer system (two drug and two polymer layers) allowed providing about constant drug release during 8h. Compared to previously proposed coated pellets aiming at constant release of freely water-soluble drugs based on non-homogeneous initial drug distribution, the total coating level in this study was very much reduced to only about 20%. Hence, the suggested formulation approach is relatively simple and can help overcoming a potentially major hurdle in practice. Its applicability has also been demonstrated for another type of drug propranolol hydrochloride.