Polyethylene oxide (PEO) has been extensively used as an extended -release excipient in matrix tablets due to its extraordinarily safe, stable, soluble, swellable and erodible properties. The present study aimed to develop once daily sustained -release tablets using PEO for a highly water-soluble drug, diltiazem hydrochloride (DH), the clinical application of which is limited because of its short half-life in vivo. However, the prophase study demonstrated that the use of PEO alone could only retard the drug release to 8 h. Thus, we proposed its combined use with chitosan/sodium alginate and formulated ternary matrix tablets by direct compression, in the hope of further extending the release of DH. The in vitro release study demonstrated that the ternary matrix synergistically prolonged DH release to 24 h while the kinetic mechanism study showed that its release was correlated with Korsmeyer-Peppas models and a non-Fickian drug release mechanism. Its release was primarily governed by diffusion and secondarily by erosion. The results of the present study demonstrated for the first time the feasibility of using a ternary hybrid matrix to prolong the release of highly water-soluble drugs, at least in the case of DH, which has a solubility as high as 625 mg/mL. (C) 2016 Elsevier B.V. All rights reserved.