The aim of the present investigation was to develop sustained release ethylcellulose-coated egg albumin microspheres of diltiazem hydrochloride (DH) to improve patient compliance. The microspheres were prepared by the w/o emulsion thermal cross-linking method using different proportion of the polymer to drug ratio (1.0:1.0, 1.0:1.5 and 1.0:2.0). A 32 full factorial design was employed to optimize two independent variables, polymer to drug ratio (X1) and surfactant concentration (X2) on dependent variables, namely % drug loading, % drug release in 60 min (Y60) and the time required for 80 % drug release (t80) were selected as dependable variable. Optimized formulation was compared to its sustained release tablet available in market. The polymer to drug ratio was optimized to 1:1 at which a high drug entrapment efficiency 79.20% ± 0.7% and the geometric mean diameter 47.30 ± 1.5 mm were found. All batches showed a biphasic release pattern; initial burst release effect (55% DH in 1 h) and then were released completely within 6 h. In situ coating of optimized egg albumin DH microspheres using 7.5% ethylcellulose significantly reduced the burst effect and provided a slow release of DH for 8-10 h. Finally, it was concluded that ethylcellulose-coated egg albumin DH microspheres is suitable for oral SR devices in the treatment of angina pectoris, cardiac arrhythmias, and hypertension due to their size and release profile.