A colonic-release delivery system containing naproxen inclusion complex with 2-hydroxypropyl-beta-cyclodextrin (2-HPbetaCD) was originally proposed. The core tablets consisting of the naproxen inclusion complex and disintegrants (Ac-Di-Sol), Primojel), Avicel) or Polyplasdone) were formed by direct compression, and then coated with the polymers, either pH-dependent Eudragit S100 and/or pH-independent Eudragit RS100 with plasticizers like dibutyl sebacate (DBS) and aluminum tristearate (AT). The in vitro release characteristics were evaluated in simulated gastric fluid for 2h and then subsequently in simulated intestinal fluid for 12h. The potential histological changes were also evaluated after direct dosing of suspensions of naproxen alone and powdered mixtures of inclusion complex-loaded tablet into rat intestinal segments. No distinct colonic release was observed when disintegrants were excluded in the single-layered coated tablets regardless of coated structures, giving a zero-order fashion over 12h. The coated tablet with double-layered structures of Eudragit S100 and Eudragit RS100 was not also applicable. In contrast, colonic release was achieved when the core tablet containing inclusion complex and disintegrant was coated with only Eudragit S100 in a single-layered structure. The colonic-release tablet was resistant in gastric fluid for 2h and for 2-4h in intestinal fluid, followed by rapid release of the drug after a total of 4-6h of lag time depending on the type of disintegrants. The lag time was advanced in case of DBS while delayed in case of AT. On histological examination, the inclusion complex-loaded suspension caused less intestinal tissue damage than naproxen alone. Based on these findings, the colonic-release tablet with enteric coatings which contains inclusion complex and disintegrants could be useful to deliver drugs like naproxen to the lower small intestine and upper colon with increased dissolution and reduced intestinal tissue damage.