A new type of colon targeting system is presented, combining time-controlled and enzyme-triggered approaches. Empty capsule shells were prepared by injection molding of blends of a high-amylose starch and hydroxypropyl methylcellulose (HPMC) of different chain lengths. The dissolution/erosion of the HPMC network assures a time-controlled drug release, i.e., drug release starts upon sufficient shell swelling/dissolution/erosion. In addition, the presence of high-amylose starch ensures enzyme-triggered drug release. Once the colon is reached, the local highly concentrated bacterial enzymes effectively degrade this polysaccharide, resulting in accelerated drug release. Importantly, the concentration of bacterial enzymes is much lower in the upper gastrointestinal tract, thus enabling site-specific drug delivery. The proposed capsules were filled with acetaminophen and exposed to several aqueous media, simulating the contents of the gastrointestinal tract using different experimental setups. Importantly, drug release was pulsatile and occurred much faster in the presence of fecal samples from patients. The respective lag times were reduced and the release rates increased once the drug started to be released. It can be expected that variations in the device design (e.g., polymer blend ratio, capsule shell geometry and thickness) allow for a large variety of possible colon targeting release profiles.