This work presents a systematic optimization framework to achieve desired release rates in drug delivery devices using multi-laminated layers. A simple mathematical model is used to describe the transient mass transfer between successive layers, laminated together to form matrices with different initial concentrations, drug diffusivities and thickness. First, an efficient analytical-based optimization approach is investigated to define the optimal nonuniform initial drug distribution for constant diffusivity profile. The results obtained are in a good agreement with relevant work from the literature resorting to advanced optimal control techniques. Then, a formal dynamic optimization approach is employed, to systematically explore the synergistic benefits when all the available controllable parameters are simultaneously optimized, in order to achieve a drug release profile as close to a desired profile as possible for the entire period of operation. The optimization results lead to significantly improved constant release profiles.