Development of timely controlled-release systems for chronotherapy of propranolol with minimization of the pH effect in the simulated gastrointestinal medium

A timely controlled release dosage form with minimization of transit time and pH effects of gastrointestinal tract for chronotherapy of propranolol was developed. Ethylcellulose (EC) and Eudragit RS selected as the controlling membrane for drug-layering non-pareil seeds (NP) or extrusion-spheronized pellets incorporated with matrix materials or osmogents were characterized in the simulated gastric fluid (SGF) and pH change medium. Results demonstrated that when propranolol was layered on NP, Eudragit RS plasticized with 30% triethylcitrate (TEC) coated at 15% level could adjust a lag time close to the reference but with a slower release rate after then, while EC plasticized with HPMC could not delay drug release at a lag time close to the reference. Furthermore, EC incorporated with lactose coated on the extrusion-spheronized pellets could adjust the lag time, but a release rate correspondingly decreased with increasing lag time. Nevertheless, coating Eudragit RS on matrix pellets as controlling membrane at different levels could adjust a desired lag time with a pulsatile release pattern. However, the lag time adjusted was only within a 5 h range. Finally, coating Eudragit RS at different level on matrix pellets containing various ratio of osmogent, NaCl or lactose, could effectively adjust a desired lag time as long as 15 h with a pulsatile release pattern to accomplish the timely controlled release with minimization of the pH effects of gastrointestinal tract that could meet the clinical need for chronotherapy of propranolol.