The objective of this study was to design a time-controlled pulsatile release (TCPR) system containing propranolol (PNH) as an active pharmaceutical ingredient. Here, the developed dosage forms were coated with hydroxypropyl-methylcellulose (HPMC) and other excipients as barrier layer using dry-coated technology. The influence of HPMC, microcrystalline cellulose (MCC), and lactose in the outer coating and the coating weight on drug release were investigated. Then, a three-factor, five-level central composite design (CCD) and response surface method were used to optimize the formula of the coating. After data processing, the optimal prescription was found to be as follows: HPMC E50(X1) 86.2 mg, MCC(X2) 43.8 mg, and lactose (X3) 21.3 mg in the coating. Moreover, the in vitro tests showed that the optimized formulation of TCPR had a lag time of 4 h followed by a 4-h drug release. Also, determination of the extent of erosion of the TCPR tablets revealed that the lag time is related to the coating erosion speed. The in vivo test in beagle dogs and comparison of the parameters for the TCPR tablets and reference preparations showed significant differences for Tmax (7.83 ± 0.408 and 2 ± 0.00) and Cmax (185.45 ± 28.561 and 587 ± 45.27 ng/ml) but no significant differences in the AUC0-∞ (1757.876 ± 208.832 and 1779.69 ± 229.02 ng h/ml). These results demonstrated that the TCPR tablets successfully prolonged the lag time and controlled the release of propranolol.
Keywords: central composite design; dry coated; pharmacokinetics; propranolol; time-controlled pulsatile release.