The development of colon-targeted drug delivery systems has gained increasing attention due to their potential to improve therapeutic outcomes for local colonic diseases such as ulcerative colitis, Crohn’s disease, and colorectal cancer, as well as to enable systemic delivery of drugs that are unstable or poorly absorbed in the upper gastrointestinal tract [1]. By ensuring site-specific release, colon-targeted systems can enhance drug bioavailability and improve patient compliance. One promising strategy for achieving targeted release in the colon involves the use of pH-sensitive and enzymatically degradable polymers that respond to the unique environment of the lower gastrointestinal tract [2].

Alongside targeted release, direct compression (DC) has emerged as a preferred tablet manufacturing technique due to its simplicity, cost-effectiveness, and minimal processing steps. However, successful DC formulation heavily relies on the ability of excipients to provide sufficient flowability and compressibility [3]. Rice starch (RS) has been widely studied as a natural and biodegradable excipient. Its small particle size and irregular granule shape promote good compressibility, making it commonly used as a tablet diluent. Despite these advantages, RS generally exhibits poor flow properties and limited plastic deformation capacity, which restricts its application in DC processes [4]. Furthermore, the low resistant starch content in RS limits its effectiveness as a controlled release matrix, as it is more easily digested and lacks the structural integrity required to control drug release throughout the gastrointestinal tract [5].

To address these limitations, heat–moisture treatment (HMT), a physical modification method, has been employed to enhance resistant starch content. In this process, starch is heated at elevated temperatures, typically between 80 and 120 °C, with a limited moisture content of about 10–30 % for controlled exposure times ranging from 1 to 16 h [6]. The controlled moisture in HMT allows for sufficient molecular mobility without destroying the granule structure, which promotes reorganization of starch molecules into more tightly packed arrangements that are less susceptible to enzymatic digestion [7]. In addition, this technique has been reported to improve the plastic deformation property and tablet tensile strength of starch, thereby supporting its use in DC tablet manufacturing [8].

Another way to improve excipient functionality for DC with controlled release property is the co-processing technique. This approach combines two or more excipients at the sub-particle level to synergistically enhance functionality or mitigate undesirable properties without altering their chemical structures [9]. Co-processing with functional polymers has been reported to improve controlled release performance while also enhancing the pharmaceutical properties of the resulting materials [10,11]. Polymers with gel-forming and swelling capabilities, such as high-viscosity hydroxypropyl methylcellulose (HPMC), can help maintain tablet integrity and provide mechanical strength throughout gastrointestinal (GI) transit. Upon hydration, HPMC swells to form a viscous gel layer around the tablet surface, acting as a barrier to control drug diffusion and enabling a gradual, erosion-mediated release mechanism [12,13]. Meanwhile, pH-sensitive polymers like Eudragit® S100, an anionic copolymer of methacrylic acid and methyl methacrylate, dissolve at pH values above 7.0, making them highly suitable for colon-specific drug delivery [[14], [15], [16]].

In our previous work, we developed co-processed rice starch combined with functional polymers (HPMC and Eudragit® S100) as a multifunctional excipient for direct compression (DC) and colon-targeted delivery, focusing on optimizing excipient ratios [17]. However, the synergistic effects of resistant rice starch (RRS) co-processed with HPMC and Eudragit® S100 as a multifunctional excipient for DC and targeted colonic delivery have not yet been fully explored. Therefore, this study aimed to develop a novel co-processed excipient based on RRS modified by heat-moisture treatment (HMT) and further co-processed with high-viscosity HPMC and Eudragit® S100 using wet granulation. The optimal HMT process parameters were determined using a design of experiments (DoE) approach. The physicochemical properties of RS and its modified forms were characterized, and the pharmaceutical properties and controlled release performance of the developed excipient were systematically evaluated using the SeDeM expert system and in vitro studies with 5-aminosalicylic acid (5-ASA) as a model drug. This work proposes a versatile excipient platform that supports efficient DC manufacturing while enabling precise, targeted drug delivery to the colon.